SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center
SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center
SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center
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S C I E N T I F I C R E P O R T 2 0 0 4<br />
R E S E A R C H A C T I V I T I E S 2 0 0 2 - 2 0 0 3
I N T R O D U C T I O N A N D P R O G R E S S R E P O R T<br />
T A B L E O F C O N T E N T S<br />
INTRODUCTION AND<br />
PROGRESS <strong>REPORT</strong><br />
i<br />
LEADERSHIP<br />
vii<br />
MULTIDISCIPLINARY RESEARCH<br />
PROGRAMS<br />
<strong>Cancer</strong> Prevention and 1<br />
Control Program<br />
Clinical Oncology Research Program 33<br />
Tumor Cell Biology Program 65<br />
Tumor Immunology Program 103<br />
Viral Oncology Program 129<br />
SHARED RESOURCES<br />
Analytical Imaging Core 143<br />
Biostatistics 145<br />
Cell Purification and Banking Facility 146<br />
Clinical Research Services Resource 147<br />
DNA Core Facility 148<br />
EDITOR<br />
W. Jarrard Goodwin, M.D., F.A.C.S.<br />
Director, University of Miami<br />
<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong><br />
PRODUCTION COORDINATION<br />
Office of Research Administration<br />
Office of Marketing and Communications<br />
Sabia Communications<br />
Flow Cytometry Resource 149<br />
Gene Knockout and Transgene Facility 150<br />
Histology Research Lab Core 151<br />
Informatics 152<br />
Molecular Analysis Core 153<br />
Population Research Core 154<br />
PUBLICATIONS 155<br />
GLOSSARY 191<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
I N T R O D U C T I O N A N D P R O G R E S S R E P O R T<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
I N T R O D U C T I O N A N D P R O G R E S S R E P O R T<br />
I N T R O D U C T I O N A N D<br />
P R O G R E S S R E P O R T<br />
W. Jarrard Goodwin, M.D., F.A.C.S.<br />
Director, University of Miami <strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong><br />
INTRODUCTION<br />
Since publishing our last Scientific Report in<br />
2002, much has changed at the University of<br />
Miami <strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong>.<br />
We have recruited more than 25 new faculty<br />
members, most of whom are physician-scientists,<br />
reflecting our commitment to translational<br />
research. Our Institutional Review Board has<br />
approved and opened 160 therapeutic clinical trials.<br />
We have strengthened our five multidisciplinary<br />
research programs and opened new shared<br />
resources, most notably the Population Research<br />
Core that supports population-based cancer<br />
prevention and control research at UM/<strong>Sylvester</strong>.<br />
With assistance from the Population Research<br />
Core, we are increasing the diversity of clinical<br />
trial participants to represent the racial, ethnic,<br />
and socioeconomic composition of South<br />
Florida’s diverse and unique community. Much<br />
of this has been done under the thoughtful leadership<br />
of Joseph D. Rosenblatt, M.D., associate<br />
director, clinical and translational research, and<br />
the several senior scientists he’s already brought<br />
to South Florida. Dr. Rosenblatt joined the<br />
University of Miami School of Medicine in 2001<br />
as division chief of Hematology-Oncology.<br />
His presence can be felt everywhere.<br />
UM/<strong>Sylvester</strong>’s Best Friend<br />
Many of you may have known or heard about Jay<br />
W. Weiss, whom we often describe as the “best<br />
friend UM/<strong>Sylvester</strong> will ever have.” As chairman<br />
of the board of governors, Jay led UM/<strong>Sylvester</strong><br />
during its most challenging years, and did so with<br />
integrity, tenacity, and grace. Jay’s vision and<br />
leadership continually invigorated and inspired us<br />
to reach new heights. To Jay, who lost his battle<br />
with cancer earlier this year, and the many others<br />
who continue to support UM/<strong>Sylvester</strong> each and<br />
every day, we dedicate this report. As we continue<br />
our quest to cure cancer and to ensure the best<br />
possible quality of life for those suffering from<br />
this disease, we know we do so with the support<br />
of many friends and colleagues. During the past<br />
two years, UM/<strong>Sylvester</strong> has been the proud recipient<br />
of nearly $56 million in cancer-related<br />
research grants and more than $17 million in<br />
philanthropy (to support research). We continually<br />
are expanding our research and clinical facilities<br />
and planning for the day when we can start<br />
building much-needed new infrastructure.<br />
<strong>Cancer</strong> Incidence and Death Rates<br />
Despite all the success we’ve had as a nation and<br />
the important research that’s underway across<br />
the globe, cancer remains a threat to this society.<br />
According to the American <strong>Cancer</strong> Society, 1.3<br />
million new cancer cases will be reported this<br />
year, and Florida stands second only to California,<br />
projecting more than 96,000 new cancer<br />
cases in <strong>2004</strong>. But we have made progress, which<br />
I highlight below. According to the Annual<br />
Report to the Nation, 1 Americans’ risk of getting<br />
and dying from cancer continues to decline<br />
and survival rates for many cancers continue<br />
to improve:<br />
• Both overall observed cancer incidence rates<br />
and death rates from all cancers combined have<br />
dropped.<br />
• We’ve seen the first ever drops in lung cancer<br />
incidence rates in women.<br />
• The percentage of patients who have survived<br />
more than five years post-diagnosis has<br />
increased in the past two decades.<br />
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• Among men, cancer incidence rates have<br />
recently declined for seven of the top 15 cancer<br />
sites: lung, colon, oral cavity, leukemia, stomach,<br />
pancreas, and larynx.<br />
• In addition to lung cancer, incidence rates<br />
among women also have declined in: colon,<br />
cervix, pancreas, ovary, and oral cavity cancers.<br />
• Childhood cancers have shown some of the<br />
largest improvements in cancer survival during<br />
the past 20 years.<br />
• There are, however, wide variations in survival<br />
associated with race and ethnicity; in every<br />
racial and ethnic population, with the exception<br />
of Asian/Pacific Islander women, the risk of<br />
cancer death from all cancer sites combined was<br />
higher than the risk of death for non-Hispanic<br />
white patients.<br />
The State of Florida, the citizens of South<br />
Florida, and the University of Miami are investing<br />
heavily in translational research—with ideas<br />
flowing from the laboratory bench to the patient’s<br />
bedside and back again—which is the essence<br />
of a comprehensive cancer center, the essence of<br />
UM/<strong>Sylvester</strong>. I am proud to tell you about the<br />
important translational research underway at<br />
UM/<strong>Sylvester</strong> and the equally important basic<br />
science and cancer prevention and control<br />
research that undergirds and strengthens our<br />
efforts.<br />
PROGRESS <strong>REPORT</strong><br />
Scientists at UM/<strong>Sylvester</strong> are grouped into<br />
five multidisciplinary research programs that<br />
reflect our strengths and our priorities—<strong>Cancer</strong><br />
Prevention and Control, Clinical Oncology Research,<br />
Tumor Cell Biology, Tumor Immunology,<br />
and Viral Oncology. Our scientists work within<br />
the established research programs and with physicians<br />
in UM/<strong>Sylvester</strong>’s 15 multidisciplinary, sitebased<br />
oncology groups. Together we design and<br />
conduct the clinical trials necessary to test the<br />
value of new prevention, screening, diagnosis,<br />
and treatment protocols. Examples of significant<br />
research currently taking place at UM/<strong>Sylvester</strong><br />
are included in this report, which is organized<br />
by multidisciplinary research program. We<br />
also have provided descriptions of each of our<br />
shared resources and a list of publications by<br />
author. Several research projects of particular<br />
note are highlighted here:<br />
Research Highlights<br />
Note: More information also can be found at<br />
www.sylvester.org.<br />
• UM/<strong>Sylvester</strong> is expanding the use of a vaccine<br />
for patients with non-small cell lung cancer.<br />
It now will be administered to two new groups<br />
of patients: those who have surgery to remove<br />
lung tumors and those who complete their<br />
first cycle of standard chemotherapy. The lung<br />
cancer vaccine was developed by Eckhard R.<br />
Podack, M.D., Ph.D., UM/<strong>Sylvester</strong>’s Associate<br />
Director, Basic Science and Chairman of<br />
Microbiology and Immunology, and has been<br />
available in research protocols at UM/<strong>Sylvester</strong><br />
for more than three years. UM/<strong>Sylvester</strong> is the<br />
only facility in the United States that does immunotherapy<br />
using the B7.1 vaccine for lung<br />
cancer. Luis Raez, M.D., F.A.C.P., asssitant<br />
professor of Medicine and Epidemiology and<br />
Public Health, administered the vaccine to 19<br />
people who had an expected survival of less<br />
than six months; six or them are still diseasefree<br />
and three have surpassed the three-year<br />
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mark with no sign of relapse. This disease is<br />
lethal and the average survival for this diagnosis<br />
is less than one year. The results of the threeyear<br />
study were published on July 15 in the<br />
Journal of Clinical Oncology.<br />
• A study just published in the New England Journal<br />
of Medicine could have huge implications<br />
for the thousands of children diagnosed with<br />
cancer every year, raising hope they can avoid<br />
potentially fatal cardiac problems caused by<br />
their treatment. Steven E. Lipshultz, M.D.,<br />
professor and chairman of Pediatrics at the University<br />
of Miami School of Medicine, is the lead<br />
author of the study, which reveals that using a<br />
heart-protective drug dexrazoxane (under the<br />
brand name Zinecard) before chemotherapy<br />
sharply lowered the amount of heart damage.<br />
The drug works by soaking up spare iron in the<br />
blood that normally would bind with the chemotherapy<br />
drug to produce compounds known<br />
to destroy heart muscle. The study, which began<br />
in 1995, tracked 200 childhood leukemia<br />
patients in the United States and Canada for<br />
three years.<br />
• Howard T. Petrie, Ph.D., professor of Microbiology<br />
and Immunology at the University of<br />
Miami School of Medicine, has identified a<br />
key step in the path that stem cells take in<br />
supporting the body’s immune system. His<br />
work was published in the June 16 issue of the<br />
journal Immunity. Finding a way to cultivate<br />
T-cell growth could lead to new therapies that<br />
strengthen the immune system in patients with<br />
a variety of illnesses.<br />
• A seven-year international study revealed that<br />
less-invasive laparoscopic surgery for colon<br />
cancer is just as effective as traditional open<br />
surgery when performed by an experienced surgeon—but<br />
with faster recovery times and fewer<br />
complications. Three UM/<strong>Sylvester</strong> colorectal<br />
surgeons were involved in the study, published<br />
in the New England Journal of Medicine in May<br />
<strong>2004</strong>—Michael D. Hellinger, M.D., F.A.C.S.,<br />
F.A.S.C.R.S., division chief of Colon and Rectal<br />
Surgery at the University of Miami School of<br />
Medicine; Laurence R. Sands, M.D., F.A.C.S.,<br />
F.A.S.C.R.S., and Rene F. Hartmann, M.D.,<br />
F.A.C.S., F.A.S.C.R.S. The study compared<br />
patient outcomes at three and five years after<br />
surgery and found no significant difference in<br />
recovery, relapse, or survival between the two<br />
techniques.<br />
• Izidore Lossos, M.D., associate professor of<br />
Medicine, is the lead author of a landmark<br />
lymphoma study published in April <strong>2004</strong> in<br />
the New England Journal of Medicine. The study<br />
identifies six genes that can predict whether a<br />
patient’s lymphoma will respond to standard<br />
treatment. This finding by researchers at the<br />
University of Miami School of Medicine,<br />
Stanford University School of Medicine, and<br />
Applied Biosystems could result in the first<br />
gene-based screening to identify people who<br />
need aggressive therapy.<br />
• Glen N. Barber, Ph.D., professor of Microbiology<br />
and Immunology and co-leader of the Viral<br />
Oncology Program at UM/<strong>Sylvester</strong>, is conducting<br />
research into using the tumor destroying<br />
properties of viruses for therapeutic purposes.<br />
This research has focused on a recombinant<br />
vesicular stomatitis virus (VSV) that expresses<br />
virus-like particles (VLP). VLP may be used<br />
for immunizing, preventing, or treating viral<br />
infections. Dr. Barber has demonstrated the<br />
feasibility of generating large amounts of VLP,<br />
including human T-lymphotropic virus, type 1<br />
and human papilloma virus-like particles using<br />
VSV, which is innocuous in humans. Furthermore,<br />
he has shown that the VLP can be delivered<br />
to dendritic cells, which in turn process<br />
and present antigens. This approach may lead<br />
to novel immunization and treatment modalities<br />
for a variety of viral infections and new<br />
approaches to cancer.<br />
• UM/<strong>Sylvester</strong> has opened a phase II clinical<br />
trial to investigate a novel treatment for metastatic<br />
melanoma. Pegylated arginine deiminase<br />
(ADI-PEG) is an amino acid enzyme inhibitor,<br />
which interferes with the ability of melanoma<br />
tumor cells to proliferate. Lynn G. Feun, M.D.,<br />
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professor of Medicine at the University of<br />
Miami School of Medicine, is leading the<br />
investigation. ADI-PEG is a targeted approach<br />
to fighting cancer, which focuses on enzymes<br />
that are very common in all melanoma cell<br />
lines. ADI-PEG attaches to arginine, an amino<br />
acid in the blood, which malignant tumor cells<br />
rely on to grow. The ADI-PEG degrades the<br />
arginine, making it impossible for the cancer<br />
to synthesize and use. This has significant advantages<br />
over previous treatments. Because<br />
this treatment is not chemotherapy, it can be<br />
administered as an outpatient treatment with<br />
a single weekly injection, rather than requiring<br />
a hospital stay or a long infusion.<br />
• Sheldon Greer, Ph.D., professor of Microbiology<br />
and Immunology at the University of<br />
Miami School of Medicine, has made many<br />
important discoveries in the course of his distinguished<br />
scientific career. An experimental<br />
radiosensitizer developed by Dr. Greer will<br />
shortly enter a phase I clinical trial for head<br />
and neck cancer patients. Cytochlor, developed<br />
by Dr. Greer and NCI-approved for patient<br />
trials to be conducted by Luis E. Raez, M.D.,<br />
F.A.C.P., enters tumor cells and renders them<br />
much more susceptible to low-dose radiation.<br />
This enables a much higher success rate against<br />
cancer cells and the potential for reducing<br />
patient side effects.<br />
• Theodore J. Lampidis, Ph.D., professor of Cell<br />
Biology and Anatomy, has discovered one way<br />
to attempt to tackle the problem of targeting<br />
non-dividing tumor cells that are resistant to<br />
chemotherapy and/or radiation. He has<br />
found that slow dividing cells located in the<br />
middle of the tumor grow under low oxygen<br />
conditions (hypoxia) and differ in their metabolism<br />
of glucose from normal cells in the body.<br />
To exploit this difference, he has shown that by<br />
simply using a false sugar—2-Deoxyglucose<br />
(2-DG)—instead of glucose, the slow growing<br />
tumor cells take up more 2-DG than the slow<br />
growing normal cells and consequently starve to<br />
death. Luis E. Raez, M.D., F.A.C.P., and Shou-<br />
Ching Tang, M.D., Ph.D., have initiated the<br />
first clinical trials in lung cancer patients using<br />
this highly novel approach.<br />
• A unique peptide (IEP11) was defined by<br />
Diana M. Lopez, Ph.D., professor of Microbiology<br />
and Immunology and leader of UM/<strong>Sylvester</strong>’s<br />
Tumor Immunology Program. This<br />
peptide appears to elicit a powerful immune<br />
response in mice that have been injected with<br />
various types of tumor cells. Subsequent studies<br />
indicate that those animals that were “IEP11<br />
immunized” were found to form tumors at a<br />
greatly reduced rate. This suggests that the<br />
peptide could serve as an adjuvant treatment to<br />
enhance many cancer vaccine therapies in the<br />
treatment of a variety of tumor types. Viragen,<br />
a new biotechnology company located in<br />
Plantation, Florida, will collaborate with the<br />
University’s team to develop the peptide for<br />
use in human clinical trials.<br />
• Azorides Morales, M.D., chairman of Pathology<br />
at the University of Miami School of Medicine,<br />
has devised a way to use microwave radiation<br />
to reduce tissue pathology processing from<br />
one day to about one hour. The Jackson Health<br />
System and UM/<strong>Sylvester</strong> are the only institutions<br />
in the world offering this technique. This<br />
is not frozen section pathology, but accelerated<br />
tissue processing patented by the University of<br />
Miami, which may revolutionize the way tissues<br />
are processed, while allowing pathologists to<br />
extract vital molecular information in ways not<br />
previously possible.<br />
• Eckhard R. Podack, M.D., Ph.D., has developed<br />
a new antibody that can be used to target<br />
Hodgkin’s and non-Hodgkin’s lymphoma cells.<br />
The development of this novel antibody called<br />
SGN30, which identifies a protein on the surface<br />
of the cancer cells and “labels” the cells<br />
with an antibody therapy, allows the immune<br />
system to target them for destruction. This is a<br />
more “intelligent” treatment and should have<br />
fewer side effects than with traditional chemotherapy.<br />
Joseph D. Rosenblatt, M.D., and<br />
iv<br />
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Hugo F. Fernandez, M.D., have initiated<br />
a clinical trial using SGN30 in lymphoma<br />
patients. UM/<strong>Sylvester</strong> has collaborated<br />
with Seattle Genetics to further the investigation<br />
of SGN30.<br />
• The future of cancer treatment also may use<br />
vaccines to boost the immune system so it<br />
recognizes and kills cancer cells. Luis E. Raez,<br />
M.D., F.A.C.P., and Richard J. Thurer, M.D.,<br />
are among the physicians working with<br />
UM/<strong>Sylvester</strong> physician-scientist Eckhard R.<br />
Podack, M.D., Ph.D., to develop several new<br />
revolutionary vaccines for the treatment of<br />
lung cancer. This approach also may lead to<br />
vaccines for other cancers. Dr. Thurer is a professor<br />
of Surgery and director of the Thoracic<br />
Surgery Section.<br />
• Joseph D. Rosenblatt, M.D., UM/<strong>Sylvester</strong>’s<br />
Associate Director, Clinical and Translational<br />
Research and Division Chief of Hematology-<br />
Oncology, opened a phase I clinical trial of a<br />
novel combination therapy for patients with<br />
certain types of leukemia and lymphoma.<br />
The idea of this trial is to use an antibody,<br />
which has had some success in the treatment<br />
of these disorders, and to try and augment the<br />
effects of that antibody in combination with<br />
interleukin-2 (IL-2). Campath-1H, also called<br />
alemtuzumab, is an approved form of treatment<br />
for patients with efractory/relapsed B-cell<br />
chronic lymphocytic leukemia, T-prolymphocytic<br />
leukemia, and cutaneous T-cell lymphomas<br />
(Sezary syndrome). By using IL-2 and<br />
alemtuzumab in combination it may hasten<br />
the return of the immune system to normal<br />
by enhancing the recovery of T cells and<br />
reducing post-treatment infectious complications.<br />
The idea of combining these two drugs<br />
was developed by Dr. Rosenblatt, Edgardo<br />
Santos, M.D., and their colleagues in the<br />
department of Medicine at the University of<br />
Miami School of Medicine.<br />
• Joseph D. Rosenblatt also is leading studies<br />
related to the development of novel immunotherapeutic<br />
and gene therapy strategies for<br />
human malignancy. Dr. Rosenblatt and<br />
Khaled Tolba, M.D., assistant professor of<br />
Medicine, have studied the ability of gene<br />
therapy “vectors” derived from herpes simplex<br />
virus called HSV amplicons to augment the<br />
immune response to tumors. Together with<br />
Seung-Uon Shin, Ph.D., an expert in antibody<br />
engineering, Dr. Rosenblatt’s laboratory has<br />
developed a variety of antibody fusion proteins<br />
with potential utility in human malignancy.<br />
These include fusions with immune effector<br />
molecules such as T-cell costimulatory ligands,<br />
and/or molecules that can recruit immune cells<br />
such as chemokines. Dr. Shin also is studying<br />
a fusion of anti-tumor antibody with an antiangiogenic<br />
agent called endostatin, which<br />
improves upon the performance of either an<br />
anti-her2/neu antibody or endostatin alone<br />
in the setting of breast cancer in preclinical<br />
tumor models.<br />
• Joyce M. Slingerland, M.D., Ph.D., professor<br />
of Medicine, is directing research efforts in<br />
breast cancer and also serves as director of the<br />
Braman Family Breast <strong>Cancer</strong> Institute at<br />
UM/<strong>Sylvester</strong>, a multidisciplinary translational<br />
research institute devoted to advancing research<br />
in cancer prevention, diagnosis, and treatment.<br />
Dr. Slingerland is a recognized authority on cell<br />
cycle regulation in relation to breast cancer,<br />
with particular emphasis on the p27 cell cycle<br />
regulator. She heads a major laboratory effort<br />
and has continued to recruit key individuals<br />
to increase expertise in the areas of molecular<br />
pathology, epidemiology, and clinical trials in<br />
breast cancer.<br />
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National <strong>Cancer</strong> Institute Designation<br />
I am pleased to tell you that UM/<strong>Sylvester</strong> will<br />
seek National <strong>Cancer</strong> Institute designation in<br />
2005. Comprised of a distinguished group of<br />
physicians and scientists, the External Advisory<br />
Committee has visited UM/<strong>Sylvester</strong> twice<br />
within the past year to evaluate the progress in<br />
our multidisciplinary research programs and<br />
research initiatives. They were highly complimentary<br />
of UM/<strong>Sylvester</strong>’s continuing efforts and<br />
recommended application for the NCI-<strong>Comprehensive</strong><br />
<strong>Cancer</strong> <strong>Center</strong> designation next year.<br />
The EAC will meet with us again during the<br />
fall of <strong>2004</strong>; their advice and assistance has been<br />
invaluable.<br />
Research is curing cancer, and to further<br />
achieve that goal, UM/<strong>Sylvester</strong> continues to<br />
build upon its excellent multidisciplinary research<br />
programs and shared resources already in place.<br />
We are especially invested in the development of<br />
home grown clinical trials based on science and<br />
technology developed at the University of Miami.<br />
We continue working to bring research discoveries<br />
from the laboratory bench to the patient bedside<br />
more quickly than ever before.<br />
In Closing<br />
These are exciting times at UM/<strong>Sylvester</strong>, and<br />
I am proud to be part of such a dynamic and<br />
dedicated team. Together with support from our<br />
senior vice president for medical affairs and dean<br />
of the school of medicine, John G. Clarkson,<br />
M.D., and University of Miami President Donna<br />
E. Shalala, Ph.D., we take steps toward winning<br />
the war against cancer every day. We also work<br />
very hard to ensure the best possible quality of<br />
life for our patients. But we must continue to<br />
do more.<br />
I hope you find this report interesting and<br />
inspiring. I want to assure you that UM/<strong>Sylvester</strong>,<br />
South Florida’s only university-based cancer center,<br />
is making a difference in the lives of South<br />
Florida citizens and that we are committed to<br />
this noble cause.<br />
Thank you for your time and attention.<br />
W. Jarrard Goodwin, M.D., F.A.C.S.<br />
Director<br />
University of Miami<br />
<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong><br />
1 NCI: http://www.cancer.gov and the SEER Homepage: http://www.seer.cancer.gov. Click on “1975-2001 Report to the Nation.”<br />
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L E A D E R S H I P<br />
L E A D E R S H I P<br />
U N I V E R S I T Y O F M I A M I<br />
Donna E. Shalala, Ph.D.<br />
President<br />
U N I V E R S I T Y O F M I A M I S C H O O L O F M E D I C I N E<br />
John G. Clarkson, M.D.<br />
Senior Vice President for Medical Affairs and Dean<br />
John M. Deeley<br />
Vice President for Administration, Operations and Planning<br />
Minor W. Anderson<br />
Associate Vice President for Medical Affairs and Managing Director, University of Miami<br />
Medical Group<br />
U M / S Y L V E S T E R C O M P R E H E N S I V E C A N C E R C E N T E R<br />
As of year end, FY <strong>2004</strong><br />
EXECUTIVE COMMITTEE<br />
W. Jarrard Goodwin, M.D., F.A.C.S.<br />
Director<br />
Michael H. Antoni, Ph.D.<br />
Associate Director,<br />
<strong>Cancer</strong> Prevention and Control<br />
Dido Franceschi, M.D.<br />
Division Chief, Informatics<br />
Kelvin P. Lee, M.D.<br />
Program Co-Leader,<br />
Clinical Oncology Research<br />
Joseph A. Lucci, III, M.D.<br />
Director, Clinical Research Services Resource<br />
Arnold M. Markoe, M.D., Sc.D.<br />
Professor and Chairman, Radiation Oncology<br />
Eckhard R. Podack, M.D., Ph.D.<br />
Associate Director, Basic Science<br />
Robert S. Powell, M.Ed.<br />
Associate Director, Administration<br />
Joseph D. Rosenblatt, M.D.<br />
Associate Director,<br />
Clinical and Translational Research<br />
James J. Schlesselman, Ph.D.<br />
Division Chief, Biostatics<br />
Joyce M. Slingerland, M.D., Ph.D.<br />
Director, Braman Family Breast <strong>Cancer</strong> Institute<br />
at UM/<strong>Sylvester</strong><br />
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L E A D E R S H I P<br />
MULTIDISCIPLINARY RESEARCH<br />
PROGRAM LEADERSHIP<br />
Michael H. Antoni, Ph.D.<br />
<strong>Cancer</strong> Prevention and Control Program<br />
Joseph D. Rosenblatt, M.D.<br />
Kelvin P. Lee, M.D.<br />
Clinical Oncology Research Program<br />
Kermit L. Carraway, Ph.D.<br />
Tumor Cell Biology Program<br />
Diana M. Lopez, Ph.D.<br />
Tumor Immunology Program<br />
William J. Harrington, Jr., M.D.<br />
Glen N. Barber, Ph.D.<br />
Viral Oncology Program<br />
SHARED RESOURCE LEADERSHIP<br />
Alberto Pugliese, M.D.<br />
Beata R. Frydel, Ph.D.<br />
Analytical Imaging Core<br />
James J. Schlesselman, Ph.D.<br />
Biostatistics<br />
Kelvin P. Lee, M.D.<br />
Cell Purification and Banking Facility<br />
Joseph A. Lucci, III, M.D.<br />
James D. Hanlon, Jr., R.N.<br />
Clinical Research Services Resource<br />
Rudolf K. Werner, Ph.D.<br />
DNA Core Facility<br />
Richard L. Riley, Ph.D.<br />
Flow Cytometry Resource<br />
Thomas R. Malek, Ph.D.<br />
Gene Knockout and Transgene Facility<br />
Carol K. Petito, M.D.<br />
Histology Research Lab Core<br />
Dido Franceschi, M.D.<br />
Informatics<br />
Roland Jurecic, Ph.D.<br />
Molecular Analysis Core<br />
Michael H. Antoni, Ph.D.<br />
Dorothy F. Parker, M.H.S.<br />
Population Research Core<br />
<strong>SCIENTIFIC</strong> STEERING COMMITTEE<br />
Eckhard R. Podack, M.D., Ph.D., Chair<br />
Microbiology and Immunology<br />
Michael H. Antoni, Ph.D.<br />
Psychology<br />
Glen N. Barber, Ph.D.<br />
Microbiology and Immunology<br />
Kermit L. Carraway, Ph.D.<br />
Cell Biology and Anatomy<br />
Murray P. Deutscher, Ph.D.<br />
Biochemistry and Molecular Biology<br />
Marilyn Stern Emas, M.Ed.<br />
Development<br />
Lora E. Fleming, M.D., Ph.D., M.P.H., M.Sc.<br />
Epidemiology and Public Health<br />
W. Jarrard Goodwin, M.D., F.A.C.S.<br />
Otolaryngology<br />
James D. Hanlon, Jr., R.N.<br />
Clinical Research Services Resource<br />
William J. Harrington, Jr., M.D.<br />
Medicine<br />
Judith B. Hayden, M.B.A.<br />
Marketing and Communications<br />
Denise M. Korniewicz, D.N.Sc., R.N., F.A.A.N.<br />
Nursing<br />
David J. Lee, Ph.D.<br />
Epidemiology and Public Health<br />
Kelvin P. Lee, M.D.<br />
Microbiology and Immunology<br />
Robert B. Levy, Ph.D.<br />
Microbiology and Immunology<br />
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L E A D E R S H I P<br />
Diana M. Lopez, Ph.D.<br />
Microbiology and Immunology<br />
Joseph A. Lucci, III, M.D.<br />
Obstetrics and Gynecology<br />
Gary S. Margules, Ph.D.<br />
Technology Transfer<br />
Robert S. Powell, M. Ed.<br />
Administration<br />
Joseph D. Rosenblatt, M.D.<br />
Medicine<br />
Antonieta Sauerteig, M.S.<br />
Research Administration<br />
James J. Schlesselman, Ph.D.<br />
Epidemiology and Public Health<br />
Joyce M. Slingerland, M.D., Ph.D.<br />
Medicine<br />
Richard Spring<br />
UM/<strong>Sylvester</strong> Board of Governors<br />
BOARD OF GOVERNORS<br />
Joaquin F. Blaya, Chair<br />
Rose Ellen Greene, Vice Chair<br />
Thomas B. Levinson, Vice Chair<br />
Diane Abrams<br />
William H. Allen, Jr.<br />
Minor Anderson<br />
Cynthia L. Augustyn, J.D.<br />
Jose P. Bared<br />
Gloria Berkowitz<br />
Norman L. Braman<br />
Minette Brown<br />
John G. Clarkson, M.D.<br />
Diane M. Cook<br />
John M. Deeley<br />
Denny Feinsilver<br />
Michael B. Fernandez<br />
Thomas J. Fitzpatrick<br />
Bernard J. Fogel, M.D.<br />
Gail Gidney<br />
W. Jarrard Goodwin, M.D., F.A.C.S.<br />
Mark Halpern<br />
Peggy Hollander<br />
Mark Levitats<br />
Alan S. Livingstone, M.D., F.A.C.S.<br />
Jayne S. Malfitano<br />
George Mencio, Jr.<br />
Eugene K. Montoya<br />
Marvin O’Quinn<br />
Dennis Patin, M.D.<br />
Nilda P. Peragallo, Dr.P.H., R.N., F.A.A.N.<br />
Joseph D. Rosenblatt, M.D.<br />
Joan Scheiner<br />
John Schulte<br />
Anne Smith, R.N., M.B.A.<br />
Richard Spring<br />
David L. Stansberry, M.S.<br />
Barbara Weintraub<br />
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ix
L E A D E R S H I P<br />
EXTERNAL ADVISORY COMMITTEE<br />
Albert F. LoBuglio, M.D.<br />
Evalina B. Spencer Professor of Oncology<br />
University of Alabama at Birmingham<br />
Director, UAB <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong><br />
David W. Golde, M.D.<br />
Enid A. Haupt Chair of Hematologic Oncology<br />
Memorial Sloan-Kettering <strong>Cancer</strong> <strong>Center</strong><br />
Head, Laboratory of Molecular and Cellular<br />
Hematology<br />
Harvey Herschman, Ph.D.<br />
Director for Basic Research<br />
Professor, Department of Biological Chemistry<br />
Professor, Department of Pharmacology<br />
UCLA-Jonsson <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong><br />
Paul B. Jacobsen, Ph.D.<br />
Professor of Psychology and Oncology<br />
University of South Florida<br />
Program Leader, Psychosocial and Palliative<br />
Care Program<br />
Program Leader, Health Outcomes and Behavior<br />
H. Lee Moffitt <strong>Cancer</strong> <strong>Center</strong> & Research Institute<br />
James J. Mulé, Ph.D.<br />
Associate <strong>Center</strong> Director, Translational Science and<br />
Technology Development<br />
Michael McGillicuddy Endowed Chair, Melanoma<br />
Research and Treatment<br />
H. Lee Moffitt <strong>Cancer</strong> <strong>Center</strong> & Research Institute<br />
Joyce C. Niland, Ph.D.<br />
Chair and Professor, Division of Information<br />
Sciences<br />
Director, Department of Biostatistics<br />
City of Hope National Medical <strong>Center</strong><br />
Paul Okunieff, M.D.<br />
Chair and Philip Rubin Professor of Radiation<br />
Oncology<br />
University of Rochester<br />
Max S. Wicha, M.D.<br />
Director, University of Michigan <strong>Cancer</strong> <strong>Center</strong><br />
Distinguished Professor of Oncology<br />
University of Michigan <strong>Cancer</strong> <strong>Center</strong><br />
James F. Lynch, M.B.A.<br />
Vice President, Hospital and Medical Science<br />
Administration<br />
Fox Chase <strong>Cancer</strong> <strong>Center</strong><br />
Nancy Mueller, Sc.D.<br />
Professor of Epidemiology<br />
Associate Director for Population Sciences<br />
Dana-Farber/Harvard <strong>Cancer</strong> <strong>Center</strong><br />
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C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
C A N C E R P R E V E N T I O N A N D<br />
C O N T R O L P R O G R A M<br />
PROGRAM LEADER<br />
Michael H. Antoni, Ph.D.<br />
Professor of Psychology<br />
DESCRIPTION OF PROGRAM<br />
The <strong>Cancer</strong> Prevention and Control Program<br />
is composed of 23 faculty members in nine<br />
different departments at the University of Miami.<br />
The program, which builds on earlier work,<br />
includes research in cancer etiology, prevention,<br />
early detection, education/outreach, cancer<br />
genetics, quality of life, survivorship, psychoneuroimmunology,<br />
and biobehavioral<br />
interventions.<br />
Specific studies underway at this time<br />
include the use of tobacco, assessment of quality<br />
of life among persons who have been treated for<br />
cancer, stress management intervention in persons<br />
recently diagnosed with cancer, investigations<br />
of cancer incidence in Florida, outreach<br />
to Hispanic populations, and implementation<br />
of cancer control strategies.<br />
The projects performed by members of the<br />
<strong>Cancer</strong> Prevention and Control Program vary<br />
substantially. Some are purely behavioral or psychosocial<br />
in their aims; others examine neuroendocrine<br />
and immunological mechanisms relevant<br />
for disease promotion and/or progression. Most<br />
of these projects entail collaboration among behavioral<br />
scientists, surgeons, and oncologists.<br />
Others involve collaboration among psychologists,<br />
epidemiologists, immunologists, biochemists,<br />
and other biomedical scientists.<br />
GOALS OF PROGRAM<br />
1) Determine the predictors of cancer risk behavior<br />
in vulnerable populations and then develop<br />
and evaluate culturally competent interventions<br />
to prevent cancer in clinical and community<br />
populations.<br />
2) Develop and evaluate psychosocial interventions<br />
designed to reduce stress, enhance quality<br />
of life, and improve compliance as well as<br />
other health-related behaviors and biological<br />
processes associated with health outcomes.<br />
3) Examine the interactive effects of stress, behavior,<br />
and psychosocial components on neuroendocrine<br />
and immune function in cancer<br />
patients and in at-risk populations. Determine<br />
how these vary across sites, gender, age, race/<br />
ethnicity, and prognostic variables.<br />
4) Better understand the risk factors for recurrence,<br />
enhancing quality of life, the role of the<br />
family in survival, preventing second malignancies<br />
and the sequelae of cancer treatment,<br />
and gain a better understanding of potential<br />
psychosocial influences on biological processes<br />
that may be involved in cancer recurrence.<br />
5) Develop and evaluate methods of disseminating<br />
cancer information and education for<br />
diverse communities.<br />
PARTICIPANTS<br />
Antoni, Michael H., Ph.D.<br />
Psychology<br />
Armstrong, F. Daniel, Ph.D.<br />
Pediatrics<br />
Baumbach-Reardon, Lisa L., Ph.D.<br />
Pediatrics<br />
Blomberg, Bonnie B., Ph.D.<br />
Microbiology and Immunology<br />
Carver, Charles S., Ph.D.<br />
Psychology<br />
Fleming, Lora E., M.D., Ph.D., M.P.H., M.Sc.<br />
Epidemiology and Public Health<br />
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Fletcher, Mary Ann A., Ph.D.<br />
Microbiology and Immunology<br />
Goodman, Kenneth W., Ph.D.<br />
Medicine<br />
Goodwin, W. Jarrard, M.D., F.A.C.S.<br />
Otolaryngology<br />
Ironson, Gail H., M.D., Ph.D.<br />
Psychology<br />
Kirsner, Robert S., M.D.<br />
Dermatology and Cutaneous Surgery<br />
Kumar, Mahendra, Ph.D.<br />
Psychiatry and Behavioral Sciences<br />
Lechner, Suzanne C., Ph.D.<br />
Psychiatry and Behavioral Sciences<br />
Lee, David J., Ph.D.<br />
Epidemiology and Public Health<br />
Levis-Dusseau, Silvina, M.D.<br />
Medicine<br />
McCoy, Clyde B., Ph.D.<br />
Epidemiology and Public Health<br />
Penedo, Frank J., Ph.D.<br />
Psychology<br />
Roos, Bernard A., M.D.<br />
Medicine<br />
Schlesselman, James J., Ph.D.<br />
Epidemiology and Public Health<br />
Schneiderman, Neil, Ph.D.<br />
Psychology<br />
Shor-Posner, Gail S., Ph.D.<br />
Psychiatry and Behavioral Sciences<br />
Twiggs, Leo B., M.D.<br />
Obstetrics and Gynecology<br />
Wilkinson, James D., M.D., M.P.H.<br />
Epidemiology and Public Health<br />
HIGHLIGHTS<br />
Breast <strong>Cancer</strong><br />
African-American women with pre-menopausal<br />
breast cancer have characteristic mutations and<br />
polymorphic variants not observed in Caucasians.<br />
In addition, the frequency of BRCA1 and<br />
BRCA2 germ-line “deleterious” mutations is<br />
much less than that observed in Caucasians.<br />
Overall, breast cancer in African-American<br />
women occurs at a younger age, is more often<br />
estrogen receptor negative, and more frequently<br />
exhibits aggressive biological behaviors.<br />
Breast <strong>Cancer</strong> Screening<br />
After controlling for demographic variables traditionally<br />
related to breast cancer screening rates,<br />
there are ethno-regional differences in breast cancer<br />
screening and Pap smear practices among Cubans,<br />
Mexican-Americans, Puerto Ricans, Central<br />
Americans, and South Americans across the United<br />
States. Social integration appears to influence<br />
participation in cancer screening among Hispanic<br />
women. The modest effect is not universal across<br />
Hispanic groups and is stronger for Pap smear<br />
than for mammography screening behavior.<br />
Florida <strong>Comprehensive</strong> <strong>Cancer</strong> Control<br />
Initiative<br />
The Florida <strong>Comprehensive</strong> <strong>Cancer</strong> Control Initiative<br />
(FCCCI) was established in October 2000<br />
as the result of a federal appropriation and funding<br />
from the CDC’s <strong>Comprehensive</strong> <strong>Cancer</strong><br />
Control Program. The CDC’s funding ended in<br />
June 2003, but the program continues as a departmental<br />
resource for expanding UM/<strong>Sylvester</strong>’s<br />
community-based cancer control research program.<br />
During the two and one-half years the FCCCI<br />
was funded by CDC, it established four regional<br />
cancer control collaboratives that cover the entire<br />
state of Florida. Each collaborative engaged in a<br />
strategic planning process and developed a comprehensive<br />
cancer control plan for their respective<br />
regions (http://fccci.med.miami.edu). More than<br />
200 individuals and 100 organizations participated<br />
in the planning process, which has been<br />
integrated into the state’s cancer control planning<br />
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activities. The regional collaboratives form a<br />
unique infrastructure that continues under the<br />
leadership of cancer centers and universities:<br />
UM/<strong>Sylvester</strong> is the lead agency for the Southeast<br />
Regional Collaborative; the H. Lee Moffitt <strong>Cancer</strong><br />
<strong>Center</strong> and Research Institute is sponsoring<br />
the Southwest Regional Collaborative; the M.D.<br />
Anderson <strong>Cancer</strong> <strong>Center</strong> in Orlando is sponsoring<br />
the Northeast Regional Collaborative; and<br />
the Northwest Regional Collaborative is led by a<br />
collaborative effort involving Florida State University,<br />
Florida A&M University, and the Coastal<br />
<strong>Cancer</strong> Information Service Partnership Program.<br />
Membership in the regional collaboratives, implementation<br />
of the regional plans, and integration<br />
into state activities, are ongoing.<br />
In addition to establishing the collaboratives<br />
and developing the regional plans, the FCCCI<br />
has conducted the following pilot studies:<br />
• Telephone survey on attitudes and barriers to cancer<br />
screening and education—a random statewide<br />
phone survey that asked participants their reasons<br />
for obtaining or not obtaining specific<br />
cancer screening tests and information about<br />
cancer.<br />
• Miami-Dade <strong>Cancer</strong> Prevention Project—addresses<br />
cancer disparities in the Haitian-American<br />
community in north Miami-Dade County,<br />
which has a high percentage of late stage diagnoses<br />
for breast, cervical, prostate, colorectal,<br />
and lung cancers.<br />
• Sun protection in Miami-Dade County public<br />
schools—a survey in elementary and middle<br />
public schools to determine current policies and<br />
procedures for protecting students and staff<br />
from sun exposure and skin cancer risk.<br />
• Small area analysis of cancer and demographic<br />
data for Miami-Dade County (funded by an<br />
American <strong>Cancer</strong> Society Florida Division<br />
grant; Robert S. Kirsner, M.D., is the principal<br />
investigator)—developed a methodology to<br />
correlate late stage diagnosis with sociodemographic<br />
variables and identify geographic areas<br />
of the county at greatest need of interventions<br />
to reduce late diagnosis.<br />
Head and Neck <strong>Cancer</strong><br />
Supplemental beta-carotene has no significant<br />
effect on second head and neck cancer mortality<br />
or lung cancer mortality.<br />
Hepatocellular Carcinoma<br />
Florida Blacks and Hispanics are at significantly<br />
increased risk for hepatocellular carcinoma (HCC)<br />
incidence when compared with Whites from<br />
Florida. These results have implications for preventive<br />
HCC recommendations in growing racial<br />
and ethnic subpopulations in the United States.<br />
Hodgkin’s Disease<br />
The incidence of Hodgkin’s and non-Hodgkin’s<br />
lymphoma is significantly higher among Florida’s<br />
Hispanic children, with 30 percent increased relative<br />
risk, compared to White non-Hispanics.<br />
Black children have significantly decreased incidence<br />
and risk. Results for lymphoid leukemia<br />
were similar. Incidence of lymphoma in Florida’s<br />
Hispanic children (primarily those of Cuban and<br />
Central American origin) differ from similar reports<br />
from Texas and California, where Hispanics<br />
are primarily of Mexican origin.<br />
Tobacco Use<br />
Results of the evaluation of Florida’s Tobacco Pilot<br />
Program show that there has been a decrease<br />
in the prevalence of smoking among middle and<br />
high school students by approximately 40 percent<br />
and 18 percent, respectively, statewide since<br />
1988. Exposure to tobacco use prevention education<br />
has been associated with lower proportions<br />
of youth who smoke, as has been the intensity of<br />
law enforcement efforts. Evaluation of the media<br />
campaign shows an association between more<br />
recall of anti-tobacco messages and less tobacco<br />
use. Further, when anti-tobacco community partnerships/coalitions<br />
were most active, there were<br />
greater decreases in youth tobacco use than when<br />
the activities were less active.<br />
Cigarette smoking may be a gateway drug to<br />
illegal drug use. Persons who had smoked cigarettes<br />
were far more likely to use cocaine, heroin,<br />
crack, and marijuana.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 3
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
MICHAEL H. ANTONI, PH.D.<br />
Professor of Psychology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Antoni’s research interests over the past<br />
decade have focused on examining the effects<br />
of stressors and stress management interventions<br />
on the adjustment to, and physical course<br />
of, diseases such as breast cancer, cervical cancer,<br />
prostate cancer, chronic fatigue syndrome, and<br />
HIV infection. He also has examined some of the<br />
psychobiological mechanisms that might explain<br />
ways in which stressful events and psychosocial<br />
interventions contribute to the adjustment to,<br />
and physical course of, these diseases looking specifically<br />
at psychological intervening variables<br />
(stress appraisal processes, coping behaviors, and<br />
social resources) and biological/physiological variables<br />
(endocrine and immune system functioning).<br />
For the past four years, Dr. Antoni has been<br />
funded by the NCI through a five-year P50 <strong>Center</strong><br />
for Psycho-Oncology Research (CPOR) grant,<br />
which conducts bio-psychosocial research on the<br />
inter-relationships between cognition, emotions,<br />
biological processes, and physical health in the<br />
context of several cognitive-behavioral stress<br />
management (CBSM) randomized clinical trials.<br />
Populations include those at high risk for cancer<br />
and those dealing with cancer diagnoses including<br />
cervical neoplasia, breast cancer, and prostate<br />
cancer. The grant includes funding for four clinical<br />
trials, five core laboratories dedicated to providing<br />
psychosocial and biological mechanism<br />
and outcome data, as well as statistical/data management<br />
for the four clinical trials. A number of<br />
UM/<strong>Sylvester</strong> investigators including those from<br />
the departments of Microbiology and Immunology,<br />
Psychology, and Medicine, have ongoing<br />
pilot studies designed to elaborate on biopsychosocial<br />
pathways being explored in the<br />
CPOR parent trials.<br />
Generally speaking, most of Dr. Antoni’s research<br />
efforts have focused on using information<br />
derived from studies examining the effects of field<br />
and laboratory stressors to develop stress reduction<br />
interventions that are specifically tailored to<br />
the disease-related issues, educational levels, and<br />
cultural characteristics of the target groups. This<br />
has resulted in the development of treatment<br />
manuals used for conducting intervention<br />
groups, which are in turn used to test the efficacy<br />
of treatment programs in the context of randomized<br />
clinical trials. In addition to testing the efficacy<br />
of these interventions in homogeneous<br />
populations, this program also will conduct<br />
generalizability studies designed to see how well<br />
the interventions work in diverse patients groups<br />
(e.g., inner city HIV+ women at risk for cervical<br />
cancer and Spanish-speaking breast cancer patients).<br />
The overarching goal is to develop theoretically<br />
driven and empirically supported<br />
psychosocial interventions with utility for secondary<br />
and tertiary prevention in persons diagnosed<br />
and treated for cancer.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,<br />
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,<br />
Schneiderman, N, and Fletcher, MA. Stress management<br />
and immune system reconstitution in<br />
symptomatic HIV-infected gay men over time:<br />
effects on transitional naïve T cells<br />
(CD4(+)CD45RA(+)CD29(+)). American Journal<br />
of Psychiatry 159:143-45, 2002.<br />
Knippels, HM, Goodkin, K, Weiss, JJ, Wilkie,<br />
FL, and Antoni, MH. The importance of cognitive<br />
self-report in early HIV-1 infection: validation<br />
of a cognitive functional status subscale.<br />
AIDS 16:259-67, 2002.<br />
Culver, JL, Arena, PL, Antoni, MH, and Carver,<br />
CS. Coping and distress among women under<br />
treatment for early stage breast cancer: comparing<br />
African Americans, Hispanics and non-Hispanic<br />
Whites. Psycho-oncology 11:495-504, 2002.<br />
4<br />
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Cruess, S, Antoni, MH, Hayes, A, Penedo, F,<br />
Ironson, G, Fletcher, MA, Lutgendorf, S, and<br />
Schneiderman, N. Changes in mood and depressive<br />
symptoms and related change processes<br />
during cognitive behavioral stress management<br />
in HIV-Infected Men. Cognitive Therapy and<br />
Research 26:373-392, 2002.<br />
Kumar, M, Kumar, AM, Waldrop, D, Antoni,<br />
MH, Schneiderman, N, and Eisdorfer, C. The<br />
HPA axis in HIV-1 infection. Journal of Acquired<br />
Immune Deficiency Syndromes 31<br />
Supplement 2:S89-93, 2002.<br />
2003<br />
Antoni, MH. Stress management and psychoneuroimmunology<br />
in HIV infection. CNS<br />
Spectrums 8:40-51, 2003.<br />
Perna, FM, Antoni, MH, Baum, A, Gordon, P,<br />
and Schneiderman, N. Cognitive behavioral<br />
stress management effects on injury and illness<br />
among competitive athletes: a randomized clinical<br />
trial. Annals of Behavioral Medicine 25:66-<br />
73, 2003.<br />
Antoni, MH. Psychoneuroendocrinology and<br />
psychoneuroimmunology of cancer: Plausible<br />
mechanisms worth pursuing? Brain, Behavior and<br />
Immunity 17 (1 Supplement):S84-91, 2003.<br />
Antoni, MH and Pitts, M. Journal of Psychosomatic<br />
Research, special issue. Journal of Psychosomatic<br />
Research 54:179-83, 2003.<br />
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,<br />
MA, Klimas, N, Duran, R, Ironson, G, and<br />
Schneiderman, N. Sleep disturbance mediates the<br />
association between psychological distress and<br />
immune status among HIV-positive men and<br />
women on combination antiretroviral therapy.<br />
Journal of Psychosomatic Research 54:185-89,<br />
2003.<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, Fletcher, MA, and<br />
O’Sullivan, MJ. Stress as a predictor of symptomatic<br />
genital herpes virus recurrence in women<br />
with human immunodeficiency virus. Journal of<br />
Psychosomatic Research 54:237-44, 2003.<br />
Petronis, VM, Carver, CS, Antoni, MH, and<br />
Weiss, S. Investment in body image and psychosocial<br />
well-being among women treated for early<br />
stage breast cancer: partial replication and extension.<br />
Psychology & Health 18:1-13, 2003.<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life<br />
stress and cervical squamous intraepithelial lesions<br />
in women with human papillomavirus and<br />
human immunodeficiency virus. Psychosomatic<br />
Medicine 65:427-34, 2003.<br />
Weiss, JL, Mulder, CL, Antoni, MH, De<br />
Vroome, EM, Garssen, B, and Goodkin, K. Effects<br />
of a supportive-expressive group intervention<br />
on long-term psychosocial adjustment in<br />
HIV-infected gay men. Psychotherapy and Psychosomatics<br />
72:132-40, 2003.<br />
McGregor, BA, Antoni, MH, Boyers, A, Alferi,<br />
SM, Blomberg, BB, and Carver, CS. Cognitive<br />
behavioral stress management increases benefit<br />
finding and immune function among women<br />
with early stage breast cancer. Journal of Psychosomatic<br />
Research 54:1- 8, 2003.<br />
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,<br />
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,<br />
and Schneiderman, N. Psychological distress is<br />
associated with decreased memory helper T-cell<br />
and B-cell counts in pre-AIDS HIV seropositive<br />
men and women but only in those with low viral<br />
load. Psychosomatic Medicine 65:627-35, 2003.<br />
O’Cleirigh, C, Ironson, G, Antoni, MH,<br />
Fletcher, MA, McGuffey, L, Balbin, E,<br />
Schneiderman, N, and Solomon, G. Emotional<br />
expression and depth processing of trauma and<br />
their relation to long-term survival in patients<br />
with HIV/AIDS. Journal of Psychosomatic Research<br />
54:225-35, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 5
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
Robbins, M, Szapocznik, J, Tejeda, M, Samuels,<br />
D, Ironson, G, and Antoni, MH. The protective<br />
role of the family and social support network in a<br />
sample of HIV+ African American women:<br />
results of a pilot study. Journal of Black Psychology<br />
29:17-37, 2003.<br />
Lechner, SC, Antoni, MH, Lydston, D,<br />
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,<br />
Schneiderman, N, Brondolo, E, Tobin, J, and<br />
Weiss, S. Cognitive-behavioral interventions improve<br />
quality of life in women with AIDS. Journal<br />
of Psychosomatic Research 54: 253-261,<br />
2003.<br />
Lechner, SC, Zakowski, SG, Antoni, MH,<br />
Greenhawt, M, Block, K, and Block, P. Do<br />
sociodemographic and disease-related factors influence<br />
benefit-finding in cancer patients?<br />
Psycho-oncology 12: 491-499, 2003.<br />
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,<br />
Carver, CS, Antoni, MH, Roos, BA, and<br />
Schneiderman, N. Perceived stress management<br />
skill mediates the relationship between optimism<br />
and positive mood following radical prostatectomy.<br />
Health Psychology 22:220-2, 2003.<br />
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni,<br />
MH, Malow, R, Costa, P, and Schneiderman, N.<br />
Personality, quality of life and HAART adherence<br />
among men and women living with HIV/AIDS.<br />
Journal of Psychosomatic Research 54:271-8,<br />
2003.<br />
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,<br />
Antoni, MH, Ironson, G, Malow, R, and<br />
Schneiderman, N. Coping and psychological distress<br />
among symptomatic HIV+ men who have<br />
sex with men. Annals of Behavioral Medicine<br />
25:203-13, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Life stress and stress management in the promotion<br />
of human papillomavirus to cervical neoplasia—<br />
researchers have been investigating the interaction<br />
of viral and psychosocial risk factors for<br />
cervical cancer among African American<br />
women who are co-infected with HIV-1 and<br />
high versus low-risk human papillomavirus<br />
(HPV) types. One study specifically examines<br />
the relationships between life stress, pessimism,<br />
emotional expression, natural killer cell cytotoxicity<br />
(NKCC), and cytotoxic-suppressor<br />
T cells, and the development of squamous<br />
intraepithelial lesions (SIL) and cervical carcinoma<br />
in women co-infected with HIV and one<br />
or more HPV types. Dr. Antoni’s laboratory<br />
recently found that elevated life stress predicts<br />
greater promotion and persistence of SIL,<br />
greater numbers of genital herpes virus outbreaks,<br />
and greater declines in NK cell percentages<br />
over a one-year prospective period in<br />
women co-infected with HIV and HPV. The<br />
reductions in NK percentage appeared to explain<br />
the association between elevated life stress<br />
and SIL promotion. This work led to one of the<br />
projects in the CPOR, which evaluates the effects<br />
of CBSM intervention on distress, quality<br />
of life, NK cells, and their cytotoxicity, and the<br />
promotion of SIL and indices of clinical disease<br />
progression in HIV+HPV+ women.<br />
• Psychosocial intervention after surgery for breast<br />
cancer—the laboratory has an NCI-funded<br />
project titled “Facilitating Positive Adaptation<br />
in Women with Breast <strong>Cancer</strong>,” which examines<br />
the effects of group-based CBSM intervention<br />
on psychosocial adjustment in 200<br />
early-stage breast cancer patients in the weeks<br />
following surgery. Pilot work over the prior year<br />
established an immunologic battery for this<br />
study, which includes lymphoproliferative responses<br />
to CD3 crosslinking and associated<br />
Th1- and Th2-like cytokine production, and<br />
cytokine-stimulated NKCC to K562 targets<br />
and breast-cancer related cell lines. This work<br />
also showed that women assigned to CBSM<br />
showed increases in positive growth and opti-<br />
6<br />
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C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
mism and a decreased prevalence of clinical depression,<br />
decreases in plasma cortisol, and increases<br />
in lymphocyte proliferative responses to<br />
anti-CD3 crosslinking.<br />
• International breast cancer research—additional<br />
work with the Helen Dowling Institute in<br />
Rotterdam, Holland, focused on developing<br />
new assessment strategies for measuring emotional<br />
expression patterns and acute responses<br />
to emotionally-arousing laboratory challenges<br />
in breast cancer patients and how these change<br />
during the course of psychotherapy. They are<br />
collecting data for a Dutch <strong>Cancer</strong> Foundation<br />
(NKB)-funded study titled “Effects of group<br />
psychotherapy compared with group support in<br />
patients with early-stage breast cancer,” which is<br />
modeled after the recently funded NCI study<br />
noted above. These researchers found evidence<br />
that psychosocial intervention reduced cortisol<br />
levels and modulated the NK cell response to<br />
laboratory challenges.<br />
• Psychosocial intervention after adjuvant therapy<br />
for breast cancer—together with a team led by<br />
Gail H. Ironson, M.D., Ph.D., and Ron E. F.<br />
Durán, Ph.D., the CPOR is investigating the<br />
effects of CBSM in a randomized trial among<br />
women who completed adjuvant therapy for<br />
breast cancer within the last year. Preliminary<br />
results suggest that the intervention produces<br />
similar psychological and physiological effects<br />
to those observed in women receiving CBSM<br />
shortly after surgery.<br />
• Psychosocial intervention after surgery for prostate<br />
cancer—together with a team led by Neil<br />
Schneiderman, Ph.D., and Frank J. Penedo,<br />
Ph.D., the CPOR is investigating the effects of<br />
CBSM in a randomized trial among men recently<br />
undergoing surgery for early-stage prostate<br />
cancer. Preliminary results suggest that the<br />
intervention is successful in increasing quality<br />
of life in this population. Studies now are underway<br />
examining the biological changes that<br />
may occur concurrently with these quality of<br />
life improvements.<br />
F. DANIEL ARMSTRONG, PH.D.<br />
Professor of Pediatrics<br />
DESCRIPTION OF RESEARCH<br />
Dr. Armstrong’s major interests in cancer<br />
research are in the areas of neurocognitive<br />
late effects in children treated for brain tumors<br />
and acute lymphocytic leukemia, quality of life<br />
assessment in childhood cancer, interventions for<br />
cognitive late effects in childhood cancer survivors,<br />
and health behavior outcomes in long-term<br />
survivors of childhood cancer.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lemanek, KL, Brown, RT, Armstrong, FD,<br />
Hood, C, Pegelow, CH, and Woods, G. Dysfunctional<br />
eating patterns and symptoms of pica in<br />
children and adolescents with sickle cell disease.<br />
Clinical Pediatrics 41:493-500, 2002.<br />
Perrin, E and the Committee on Psychosocial<br />
Aspects of Child and Family Health, American<br />
Academy of Pediatrics. (Armstrong, FD, co-author),<br />
Technical Report: Co-parent or secondparent<br />
adoption by same-sex parents. Pediatrics<br />
109:341-344, 2002.<br />
2003<br />
Thompson, RJ, Jr., Armstrong, FD, Link, CL,<br />
Pegelow, CH, Moser, F, and Wang, W. A prospective<br />
study of the relationship over time of behavior<br />
problems, intellectual functioning, and family<br />
functioning in children with sickle cell disease:<br />
a report from the Cooperative Study of Sickle<br />
Cell Disease. Journal of Pediatric Psychology<br />
28:59-65, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 7
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
LISA L. BAUMBACH-REARDON, PH.D.<br />
Associate Professor of Pediatrics<br />
DESCRIPTION OF RESEARCH<br />
Dr. Baumbach’s laboratory is involved in<br />
breast cancer research focusing on a better<br />
understanding of the genetic basis of breast cancer<br />
in African-American women. The laboratory<br />
is completing two major projects. The first is the<br />
development of a specific BRCA1 and BRCA2<br />
mutation/variants panel for women of African<br />
ancestry with either breast cancer or a significant<br />
family history of breast/ovarian cancer. Development<br />
of such a panel will allow its incorporation<br />
into clinical practice with clear improvement<br />
of genetic counseling for this minority and<br />
underserved population. Based on their preliminary<br />
data, supplemented with a thorough review<br />
of all published English literature, the laboratory<br />
has identified 13 reported mutations and 13 reported<br />
unclassified variants in BRCA1, and six<br />
mutations and ten variants in BRCA2 in African<br />
Americans. Some of these genetic changes are<br />
specific to an individual; others are recurrent in<br />
the African Americans studied. A screening panel<br />
for such BRCA1 and BRCA2 mutations/variants<br />
will be designed to develop an efficient assay for<br />
eventual use in clinical practice.<br />
The second project, which complements the<br />
first, is a genome-wide analysis of all genetic<br />
changes in breast cancer tissues collected from<br />
African-American patients. These studies will use<br />
state-of-the art technology of DNA microarray<br />
analysis. The combined information from these<br />
studies will provide significant new insights into<br />
the genetic basis of African-American breast cancer,<br />
thus providing important new information<br />
regarding diagnosis and possible therapies.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Identified 13 reported mutations and 13 reported<br />
unclassified variants in BRCA1, and six<br />
mutations and 10 variants in BRCA2 in African<br />
Americans.<br />
• Made significant progress in the development of<br />
the mutation screening panel-streamlined<br />
methodology for mutation detection.<br />
• Filed for a patent to protect information related<br />
to the development of the mutation screening<br />
panel, through the University of Miami Office<br />
of Technology Transfer.<br />
• Conducted further detection and population<br />
screening for African-American BRCA1 and<br />
BRCA2 missense mutations.<br />
BONNIE B. BLOMBERG, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Research in Dr. Blomberg’s laboratory focuses<br />
on two projects. One of these projects<br />
involves basic research on the molecular regulation<br />
of B lymphopoiesis in mice. Generation of<br />
B lymphocytes is important in cancer patients<br />
receiving bone marrow as well as in the normal<br />
production of the humoral (antibody) response.<br />
Aged humans and other mammals have a poorer<br />
immune response to pathogens.<br />
In collaboration with Richard L. Riley,<br />
Ph.D., in the department of Microbiology and<br />
Immunology, Dr. Blomberg has shown that aged<br />
mice, those greater than or equal to about 80<br />
percent of their full life span, have a substantial<br />
decrease in the number of precursor B lymphocytes<br />
as well as the amount of the precursor B-cell<br />
receptor (preBCR) including the surrogate light<br />
chain (SLC)g5 and VpreB. Their data indicate<br />
that this affects the antibody V H<br />
repertoire at the<br />
pre-B cell level, i.e., before antigen selection.<br />
8<br />
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C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
More recent data indicate that the transcription<br />
factor, E2A, is reduced in not only precursor B<br />
cells but also in mature B cells in peripheral<br />
lymphoid organs in aging, leading to defects in<br />
Ig class switch and humoral immunity. Current<br />
studies will reveal the molecular and cellular<br />
causes of these defects in the aged humoral<br />
immune response and attempt to reverse these<br />
defects. These studies are important for cancer<br />
for two reasons: 1) the depressed immune<br />
response seen in aged humans likely contributes<br />
to increased susceptibility to cancer, and 2) bone<br />
marrow transplantation given to many types of<br />
cancer patients requires generation of mature<br />
B lymphocytes from the precursors in the bone<br />
marrow. Knowledge about the cellular and<br />
molecular requirements for B lymphopoiesis<br />
in young and aged individuals should lead to<br />
improvements in the humoral immune system<br />
of cancer patients.<br />
Another project in Dr. Blomberg’s laboratory<br />
involves clinical research with breast cancer patients.<br />
In collaboration with Michael H. Antoni,<br />
Ph.D., and Charles S. Carver, Ph.D., in the department<br />
of Psychology, Sharlene Weiss, Ph.D.,<br />
in the department of Medicine, and members of<br />
the <strong>Cancer</strong> Prevention and Control Program at<br />
UM/<strong>Sylvester</strong>, Dr. Blomberg’s laboratory is<br />
measuring the status of various immune parameters<br />
in patients in response to psychosocial intervention<br />
(e.g., group therapy, stress reduction).<br />
Preliminary experiments have shown that intervention<br />
patients have an improved immune<br />
response as seen by the ability of their T cells<br />
to proliferate in response to an antigen-specific<br />
receptor stimulus (anti-CD3). Current studies are<br />
measuring T, natural killer (NK), and lymphokine-activated<br />
killer (LAK) cytotoxic function<br />
as well as potential TH1/TH2 differences by<br />
cytokine production resulting from T-cell stimulation.<br />
These studies are important to allow optimal<br />
immune response in cancer patients, which<br />
will better detect/destroy residual cancer and<br />
allow for better patient survival.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Jin, Y, Fuller, L, Carreno, M, Esquenazi, V,<br />
Blomberg, BB , Wei, YT, Ciancio, G, Burke, GW<br />
3rd, Tzakis, A, Ricordi, C, and Miller, J. Functional<br />
and phenotypic properties of peripheral T<br />
cells anergized by autologous CD3(+) depleted<br />
bone marrow cells. Human Immunology 63:567-<br />
75, 2002.<br />
Burke, GW, Ciancio, C, Blomberg, BB , Rosen,<br />
A, Suzart, K, Roth, D, Kupin, W, Esquenazi, V,<br />
and Miller, J. Randomized trial of three different<br />
immunosuppressive regimens to prevent chronic<br />
renal allograft rejection. Transplantation Proceedings<br />
34:1610-11, 2002.<br />
Blomberg, BB , Mathew, J, Fainman, H, Hussini,<br />
S, Carreno, M, Hnatyszyn, H, Garcia-Morales,<br />
R, Fuller, L, Vallone, T, Rosen, A, Esquenazi, V,<br />
Ricordi, C, Tzakis, A, and Miller, J. Human bone<br />
marrow cells retrovirally transduced with the allogeneic<br />
class II gene, HLA-DR3beta, down regulate<br />
anti-allogeneic responses of autologous<br />
lymphoid cells. Human Immunology 63:S19,<br />
2002.<br />
2003<br />
Mathew, JM, Blomberg, BB , Fuller, L, Burke,<br />
GW, Ciancio, G, Kenyon, N, Ricordi, C, Tzakis,<br />
AG, Esquenazi, V, and Miller, J. A novel microcell-mediated<br />
lympholytic assay for the evaluation<br />
of regulatory cells in human alloreactive<br />
CTL responses. Journal of Immunological Methods<br />
272:67-80, 2003.<br />
Blomberg, BB , Hussini, S, Fainman, H, Mathew,<br />
JM, Hernandez, A, Carreno, M, Hnatyszyn, HJ,<br />
Garcia-Morales, R, Fuller, L, Rosen, A, Ricordi,<br />
C, Tzakis, A, Miller, J, and Esquenazi, V.<br />
Retroviral transduction of an allogeneic class II<br />
gene into human bone marrow down regulates<br />
allo-immune reactivity. Human Immunology<br />
64:S128, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 9
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
Hernandez, A, Lindner, I, Blomberg, BB,<br />
Hussini, S, Burger, M, Mathew, JM, Carreno, M,<br />
Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A,<br />
Lee, KP, Miller, J, and Esquenazi, V. Suppression<br />
of allogeneic T cell proliferation through blocking<br />
of NF-KB in the differentiation process of<br />
human dendritic cells. Human Immunology<br />
64:S128, 2003.<br />
Mathew, JM, Alvarez, S, Vallone, T, Blomberg,<br />
BB, Joshua, M, and Esquenazi, V. A human-<br />
SCID-mouse-islet transplant model for the evaluation<br />
of the regulatory activity of donor bone<br />
marrow cells. Human Immunology 64:S7, 2003.<br />
Van Der Put, E, Sherwood, EM, Blomberg, BB,<br />
and Riley, RL. Aged mice exhibit distinct B cell<br />
precursor phenotypes differing in activation, proliferation,<br />
and apoptosis. Experimental Gerontology<br />
38:1137-47, 2003.<br />
Frasca, D, Nguyen, D, Van Der Put, E, Riley,<br />
RL, and Blomberg, BB. The Age-related decrease<br />
in E47 DNA-binding does not depend on increased<br />
Id inhibitory proteins in bone marrowderived<br />
B cell precursors. Frontiers in Bioscience<br />
8:A110-16, 2003.<br />
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,<br />
BB. Effects of aging on proliferation and E47<br />
transcription factor activity induced by different<br />
stimuli in murine splenic B cells. Mechanisms of<br />
Ageing and Development 124:361-69, 2003.<br />
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,<br />
BB. Decreased E12 and/or E47 transcription factor<br />
activity in the bone marrow as well as in the<br />
spleen of aged mice. Journal of Immunology<br />
170:719-26, 2003.<br />
Frasca, D, Van der Put, E, Riley, RL, and<br />
Blomberg, BB . Reduced Ig class switch in aged<br />
mice correlates with decreased E47 and activation-induced<br />
cytidine deaminase. Journal of Immunology<br />
172:2155-62, 2003.<br />
McGregor, BA, Antoni, MH, Boyers, A, Alferi,<br />
SM, Blomberg, BB , and Carver, CS. Cognitive<br />
behavioral stress management increases benefit<br />
finding and immune function among women<br />
with early stage breast cancer. Journal of Psychosomatic<br />
Research 54:1- 8, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Compromised humoral immune response in<br />
aged individuals may be at least partially explained<br />
by antibody V H<br />
repertoire differences at<br />
the pre-B cell level (before antigen selection).<br />
• Decreased transcription factor E2A is important<br />
for decreased Ig class switch and optimal humoral<br />
immunity.<br />
• Demonstrated improved immune response in<br />
breast cancer patients after psychosocial intervention.<br />
CHARLES S. CARVER, PH.D.<br />
Professor of Psychology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Carver’s cancer-related research concerns<br />
the role of psychosocial variables in cancer<br />
morbidity and quality of life in cancer patients,<br />
in terms of emotional disturbance, psychosexual<br />
disturbance, and disruption of normal life activities.<br />
He is interested in the influences of vulnerability<br />
and resilience factors such as personality<br />
and perceptions of availability of social support.<br />
Dr. Carver also is interested in coping processes<br />
of various sorts and their influence on adaptation<br />
to diagnosis and treatment of cancer. Over time,<br />
his work has expanded to include studies of quality<br />
of life among long-term survivors of cancer<br />
and studies of relations between psychosocial<br />
variables at diagnosis and recurrence over the<br />
years following treatment (PI, Quality of Life<br />
in Adult <strong>Cancer</strong> Survivors, NCI grant R01-<br />
CA78995). Dr. Carver is a collaborator in<br />
research that provides cancer patients with<br />
psychosocial interventions—ten-week group<br />
10<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
sessions in cognitive-behavioral stress management—and<br />
examines effects of those interventions<br />
over the subsequent year. His first study on<br />
that topic examined only psychosocial outcomes<br />
(PI, Adjustment to Breast <strong>Cancer</strong> Among Younger<br />
Women, NCI grant R01- CA64710). Pilot data<br />
collected in that study, however, have led to further<br />
work in which he and his colleagues also are<br />
examining the impact of the intervention on immune<br />
function (Co-PI, Facilitating Positive Adaptation<br />
to Breast <strong>Cancer</strong>, NCI grant<br />
R01-CA64710).<br />
SELECTED PUBLICATIONS<br />
2002<br />
Perczek, RE, Burke, MA, Carver, CS, Krongrad,<br />
A, and Terris, MK. Facing a prostate cancer diagnosis:<br />
who is at risk for increased distress? <strong>Cancer</strong><br />
94:2923-29, 2002.<br />
Culver, JL, Arena, PL, Antoni, MH, and Carver,<br />
CS. Coping and distress among women under<br />
treatment for early stage breast cancer: Comparing<br />
African Americans, Hispanics, and non-Hispanic<br />
Whites. Psycho-oncology 11:495-504,<br />
2002.<br />
2003<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, Fletcher, MA, and<br />
O’Sullivan, MJ. Stress as a predictor of symptomatic<br />
genital herpes virus recurrence in women<br />
with human immunodeficiency virus. Journal of<br />
Psychosomatic Research 54:237-44, 2003.<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life<br />
stress and cervical squamous intraepithelial lesions<br />
in women with human papillomavirus and<br />
human immunodeficiency virus. Psychosomatic<br />
Medicine 65:427-34, 2003.<br />
McGregor, BA, Antoni, MH, Boyers, A, Alferi,<br />
SM, Blomberg, BB, and Carver, CS. Cognitive<br />
behavioral stress management increases benefit<br />
finding and immune function among women<br />
with early stage breast cancer. Journal of Psychosomatic<br />
Research 54:1-8, 2003.<br />
Carver, CS, Lehman, JM, and Michael, HA. Dispositional<br />
pessimism predicts illness. Journal of<br />
Personality and Social Psychology 84:813-21,<br />
2003.<br />
Petronis, VM, Carver, CS, Antoni, MH, and<br />
Weiss, S. Investment in body image and psychosocial<br />
well-being among women treated for early<br />
stage breast cancer: partial replication and extension.<br />
Psychology & Health 18:1-13, 2003.<br />
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,<br />
Carver, CS, Antoni, MH, Roos, BA, and<br />
Schneiderman, N. Perceived stress management<br />
skill mediates the relationship between optimism<br />
and positive mood following radical prostatectomy.<br />
Health Psychology 22:220-2, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Completed interviews with 90 cancer survivors,<br />
while working toward the development of a<br />
measure of psychosocial adjustment aimed<br />
specifically at cancer survivors. The interview<br />
phase was followed by an item-development<br />
phase. The items were then tested on another<br />
sample of cancer survivors, resulting in a measure<br />
termed the Quality of Life in Adult <strong>Cancer</strong><br />
Survivors (QLACS).<br />
• Investigated ethnic differences in reactions to<br />
the cancer experience. One study found that<br />
Hispanic women reported a variety of more<br />
intense concerns of several sorts than did non-<br />
Hispanic Whites or Blacks, along with greater<br />
levels of distress. Concerns about existential<br />
issues, sexuality, and rejection from others all<br />
played roles in predicting various aspects of<br />
quality of life in this study. Two other studies<br />
determined that Hispanic and African-American<br />
women use more religious coping than do<br />
non-Hispanic White women. Non-Hispanic<br />
White women, it was found, use more humor.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 11
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
• Studied a sample of low socioeconomic status<br />
(SES) Hispanic breast cancer patients. This<br />
study, led by Dr. Carver’s colleague, Susan<br />
Alferi, Ph.D., found substantial differences<br />
between women who identified themselves as<br />
Catholic and those who identified themselves<br />
as fundamentalist Christians. Among the<br />
Catholic women, greater involvement in<br />
religious coping was related to greater emotional<br />
distress. Among the other women the<br />
opposite pattern emerged. Clearly, the effect<br />
of religious involvement varies with the nature<br />
of the religious involvement.<br />
• Examined the effects of early portions of the<br />
experience on the quality of life of long-term<br />
survivors (five years or more). This research has<br />
found that higher levels of distress during the<br />
period surrounding treatment related strongly<br />
to higher levels of distress five to 15 years later.<br />
One of these studies also found that women<br />
who reported finding benefit in the cancer experience<br />
during the first year post-treatment<br />
had better emotional quality of life four to<br />
seven years later.<br />
LORA E. FLEMING, M.D., PH.D., M.P.H.,<br />
M.Sc.<br />
Professor of Epidemiology<br />
and Public Health<br />
DESCRIPTION OF RESEARCH<br />
Dr. Fleming’s research interests are focused in<br />
occupational and environmental medicine<br />
and epidemiology. She is the only board-certified<br />
and licensed occupational and enviromental<br />
medicine physician and epidemiologist in South<br />
Florida.<br />
Dr. Fleming has performed funded research<br />
on the health effects of methyl mercury contamination<br />
in the Everglades (Agency for Toxic Substances<br />
and Disease Registry and the Florida<br />
Department of Health (FDOH)); a study of fumigation<br />
workers with the National Institute of<br />
Occupational Safety and Health (NIOSH); a<br />
study of pesticide levels and Parkinson’s disease<br />
(University of Miami Glaser Award); an evaluation<br />
of reported health effects of the fumigant<br />
Benlate (FDOH); an evaluation of the human<br />
health effects of hazardous waste incineration<br />
(Florida Department of Environmental Protection);<br />
an evaluation of the occupational health<br />
effects of solid waste work (<strong>Center</strong> for Solid and<br />
Hazardous Waste); back injury prevention in<br />
firefighters (FDOH); several studies on the human<br />
health effects of the marine toxin diseases<br />
(National Institute of Environmental Health Sciences,<br />
CDC, and the FDOH); a NIOSH Career<br />
Development Award studying the chronic health<br />
effects of a large cohort of licensed Florida pesticide<br />
applicators; and has recently finished a large<br />
cohort study of certified Florida firefighters<br />
funded by NIOSH.<br />
Dr. Fleming is associate director of the<br />
NIEHS Marine and Freshwater Biomedical Sciences<br />
<strong>Center</strong> at the University of Miami and director<br />
of outreach and education at the center.<br />
She serves and has served on numerous task<br />
forces and committees, including the Florida<br />
Birth Defects Registry, Florida Harmful Algal<br />
Bloom Taskforce, and the Florida Pesticide Advisory<br />
Committee.<br />
<strong>Cancer</strong>-Related Activities<br />
At UM/<strong>Sylvester</strong>, Dr. Fleming is the director of<br />
research and project director for the Florida <strong>Cancer</strong><br />
Data System (FCDS), Florida’s incident tumor<br />
registry. As part of her work with FCDS, Dr.<br />
Fleming interacts with investigators, students, and<br />
FCDS personnel to increase research opportunities<br />
and educational outreach at the FCDS. With<br />
her colleagues, Dr. Fleming has investigated the<br />
cancer experience of Florida’s Hispanic population,<br />
the risk of subsequent cancers among persons with<br />
ovarian cancer, the risk of cancer among Florida’s<br />
children, and the stage at which poor women in<br />
Florida present for diagnosis of breast cancer.<br />
Based on her research, which focuses on the<br />
human health effects of marine and freshwater<br />
toxins, Dr. Fleming has studied the possible asso-<br />
12<br />
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C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
ciation between blue green algal toxins in drinking<br />
water and the risk of hepatocellular carcinoma<br />
in Florida.<br />
With NIOSH funding, Dr. Fleming has assisted<br />
Fangchao Ma, M.D., and other colleagues<br />
to examine the cancer risks associated with<br />
firefighting in Florida. A retrospective cohort<br />
study was conducted among 34,796 male and<br />
2,017 female firefighters certified between 1972<br />
and 1999. Age- and gender-specific cancer incidence<br />
rates in the general Florida population<br />
were used as comparisons in calculating the standardized<br />
incidence ratios (SIR). A total of 1,032<br />
cases of cancer among Florida firefighters (970<br />
male and 52 female) were identified by linkage<br />
with the FCDS as of December 31, 1999. The<br />
overall risk of cancer among male firefighters was<br />
significantly lower compared to that of the general<br />
Florida population (age adjusted SIR=0.84;<br />
95 perecent CI=0.79-0.90) as well as for cancers<br />
of buccal (0.67; 0.47-0.91), stomach (0.50; 0.25-<br />
0.90), lung (0.65; 0.54-0.78), and brain (0.58;<br />
0.31-0.97). Significantly increased cancer incidence<br />
was observed among male firefighters for<br />
bladder (1.29; 1.01-1.62), testes (1.60; 1.20-<br />
2.09), and thyroid cancers (1.77; 1.08-2.73). Female<br />
firefighters had significantly increased<br />
overall risk (1.63; 1.22-2.14), and increased incidence<br />
for thyroid cancers (3.97; 1.45-8.65) and<br />
Hodgkin’s disease (6.25; 1.26-18.26).<br />
SELECTED PUBLICATIONS<br />
2002<br />
Dewailly, E, Furgal, C, Knap, A, Galvin, J,<br />
Baden, D, Bowen, B, Depledge, M, Duguay, L,<br />
Fleming, LE, Ford, T, Moser, F, Owen, R, Suk,<br />
WA, and Unluata, U. Indicators of ocean and<br />
human health. Canadian Journal of Public<br />
Health 93: S34-8, 2002.<br />
Grant, P, Skinner, HG, Fleming, LE, and Bean,<br />
JA. Influence of structured encounter forms on<br />
documentation by community pediatricians.<br />
Southern Medical Journal 95:1026-31, 2002.<br />
Knap, A, Dewailly, E, Furgal, C, Galvin, J,<br />
Baden, D, Bowen, RE, Depledge, M, Duguay, L,<br />
Fleming, LE, Ford, T, Moser, F, Owen, R, Suk,<br />
WA, and Unluata, U. Indicators of ocean health<br />
and human health: developing a research and<br />
monitoring framework. Environmental Health<br />
Perspectives 110:839-45, 2002.<br />
Zhou, O, Shimoda, H, Gao, B, Oh, S, Fleming,<br />
LE, and Yue, G. Materials science of carbon<br />
nanotubes: fabrication, integration, and properties<br />
of macroscopic structures of carbon<br />
nanotubes. Accounts of Chemical Research<br />
35:1045-53, 2002.<br />
Wilkinson, JD, Wohler-Torres, B, Trapido, E,<br />
Fleming, LE, MacKinnon, J, and Peace, S. <strong>Cancer</strong><br />
among Hispanic women in South Florida: an<br />
18-year assessment: a report from the Florida<br />
<strong>Cancer</strong> Data System. <strong>Cancer</strong> 95:1752-58, 2002.<br />
2003<br />
Oberstein, EM, Fleming, LE, Gomez-Marin, O,<br />
and Glassberg, MK. Pulmonary Lymphangioleiomyomatosis<br />
(LAM): Examining Oral Contraceptive<br />
Pills and the Onset of Disease. Journal<br />
of Women’s Health (Larchmont) 12:81-5, 2003.<br />
Entzel, PP, Fleming, LE, Trepka, MJ, and<br />
Squicciarini, D. The health status of newly<br />
arrived refugee children in Miami-Dade County,<br />
Florida. American Journal of Public Health<br />
93:286-8, 2003.<br />
Fleming, LE, Gomez-Marin, O, Zheng, D, Ma,<br />
F, and Lee, D. National Health Interview Survey<br />
mortality among US farmers and pesticide applicators.<br />
American Journal of Industrial Medicine<br />
43:227-33, 2003.<br />
Varela, JE, Gomez-Marin, O, Fleming, LE, and<br />
Cohn, SM. The risk of death for Jehovah’s Witnesses<br />
after major trauma. Journal of Trauma<br />
54:967-72, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 13
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
HIGHLIGHTS/DISCOVERIES<br />
• Research on human health effects of marine and<br />
freshwater toxins—blue green algae, or<br />
cyanobacteria, are microorganisms at the base<br />
of the food and oxygen chain. The blue green<br />
algae easily grow in fresh water reservoirs, sometimes<br />
producing large amounts of toxins. These<br />
natural toxins can be carcinogenic and have<br />
been associated with an increased risk of liver<br />
cancer in animals and humans in China; furthermore,<br />
normal drinking water treatment<br />
does not completely remove these toxins.<br />
Therefore, using the technology of geographic<br />
information systems (GIS) to store, analyze,<br />
and display the data, Dr. Fleming and her colleagues<br />
showed that there may be an increased<br />
risk of liver cancer in Florida for persons living<br />
near surface water treatment plants with possible<br />
blue green algal toxin contamination. This<br />
study was performed in collaboration with the<br />
FCDS, the University of Miami NIEHS Marine<br />
and Freshwater Biomedical Sciences <strong>Center</strong>,<br />
and the Rosenstiel School of Marine and<br />
Atmospheric Sciences, as well as the St. Johns<br />
River Management District. Funding for this<br />
study was provided by the Florida Harmful Algal<br />
Bloom Taskforce at the Florida Marine Research<br />
Institute.<br />
• Examination of the cancer risks associated with<br />
firefighting in Florida—this study did not find<br />
evidence of an excess risk of lung or brain cancer<br />
in firefighters as documented in prior mortality<br />
studies. The study does, however, suggest<br />
that a significantly increased risk of bladder<br />
cancer among male firefighters might be related<br />
to occupational exposure, rather than tobacco<br />
use. This is the largest known study of<br />
firefighters to date.<br />
MARY ANN A. FLETCHER, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Fletcher is interested in studying immunologic<br />
changes during stress management in<br />
breast cancer and cervical neoplasia. She has collaborated<br />
with Michael H. Antoni, Ph.D., Gail H.<br />
Ironson, M.D., Ph.D., and Neil Schneiderman,<br />
Ph.D., for the past 17 years on NIH-funded<br />
projects examining the immunological effects of<br />
stress management in persons with HIV infection,<br />
women at risk for cervical cancer, and<br />
women undergoing treatment for early-to-midstage<br />
breast cancer.<br />
Dr. Fletcher is the director of the E.M.<br />
Papper Laboratory of Clinical Immunology. This<br />
laboratory has been an important core facility for<br />
mind-body research at the University of Miami<br />
for many years. Much of their research has been<br />
cancer related. Currently, the laboratory supports<br />
the P50 <strong>Center</strong> for Psycho-Oncology Research<br />
(CPOR), which is assessing the effects of cognitive-behavioral<br />
stress management (CBSM) on<br />
both psychological and biological parameters in<br />
patients with breast cancer and prostate cancer<br />
and with cervical hyperplasia. The laboratory<br />
functions as a Biological Assessment Core to<br />
coordinate the collection, storage, and assaying<br />
of immune indices of cytotoxic and helper cell<br />
function (cytokine-stimulated natural killer cytotoxicity<br />
(NKCC), ELISPOT, quantitative flow<br />
cytometric measurement of surface and intracellular<br />
molecules, including activation and differentiation<br />
markers as well as cytokines, perforin, and<br />
granzymes). By ELISA assays, the laboratory<br />
measures Th1 (g-IFN, IL-2, IL-12), Th2 (IL-4,<br />
IL-5, IL-6, and IL-10), and proinflamatory (IL-1,<br />
IL-6, and TNF-α) cytokines as well as receptors<br />
of these cytokines in body fluids and lymphocyte<br />
culture supernatants. Standardized assays are used<br />
for soluble markers of disease activity (CA 15.3,<br />
PSA, VEGF, etc.) in blood samples collected<br />
from cancer patients and controls.<br />
14<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
SELECTED PUBLICATIONS<br />
2002<br />
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,<br />
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,<br />
Schneiderman, N, and Fletcher, MA. Stress management<br />
and immune system reconstitution in<br />
symptomatic HIV-infected gay men over time:<br />
effects on transitional naive T cells<br />
(CD4(+)CD45RA(+)CD29(+)). American Journal<br />
of Psychiatry 159:143-45, 2002.<br />
2003<br />
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,<br />
MA, Klimas, N, Duran, R, Ironson, G, and<br />
Schneiderman, N. Sleep disturbance mediates the<br />
association between psychological distress and<br />
immune status among HIV-positive men and<br />
women on combination antiretroviral therapy.<br />
Journal of Psychosomatic Research 54:185-89,<br />
2003.<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, Fletcher, MA, and<br />
O’Sullivan, MJ. Stress as a predictor of symptomatic<br />
genital herpes virus recurrence in women<br />
with human immunodeficiency virus. Journal of<br />
Psychosomatic Research 54:237-44, 2003.<br />
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,<br />
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,<br />
and Schneiderman, N. Psychological distress is<br />
associated with decreased memory helper T-cell<br />
and B-cell counts in pre-AIDS HIV seropositive<br />
men and women but only in those with low viral<br />
load. Psychosomatic Medicine 65:627-35, 2003.<br />
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,<br />
MA, McGuffey, L, Balbin, E, Schneiderman, N,<br />
and Solomon, G. Emotional expression and<br />
depth processing of trauma and their relation to<br />
long-term survival in patients with HIV/AIDS.<br />
Journal of Psychosomatic Research 54:225-35,<br />
2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Dr. Fletcher’s primary areas of focus include<br />
examining quantitative indices of lymphocyte<br />
subpopulations and qualitative indices of function<br />
including NKCC and IgG antibodies to<br />
latent herpes viruses, and how these respond to<br />
stressors and stress management interventions<br />
in these populations.<br />
• Her laboratory currently is exploring the mechanics<br />
of cytotoxicity (e.g., perforin and<br />
granzyme production) and how these relate to<br />
psychosocial factors via hypothalamic pituitary<br />
adrenal hormone changes.<br />
KENNETH W. GOODMAN, PH.D.<br />
Associate Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Work on ethics and evidence-based practice<br />
constitutes a natural extension of efforts to<br />
explore ethical issues in health informatics, epidemiology,<br />
and public health. The University of<br />
Miami’s reputation as a leader in under-addressed<br />
areas of clinical and research ethics continues to<br />
expand. The University continues to work on<br />
issues in the use of information technology, especially<br />
in public health. Moreover, the University’s<br />
ethics programs include international research<br />
ethics among the core foci, even as the University<br />
continues work on end-of-life care, environmental<br />
health and ethics, and genetics. Efforts to develop<br />
ethics curricula for scientists and others<br />
continue.<br />
Dr. Goodman is director of the University of<br />
Miami’s Bioethics Program, director of clinical and<br />
research ethics education at UM/<strong>Sylvester</strong>, and<br />
vice chair of UM/<strong>Sylvester</strong>’s Bioethics Committee.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 15
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
SELECTED PUBLICATIONS<br />
2002<br />
Green, RM, DeVries, KO, Bernstein, J,<br />
Goodman, KW, Kaufmann, R, Kiessling, AA,<br />
Levin, SR, Moss, SL, and Tauer, CA. Overseeing<br />
research on therapeutic cloning: a private ethics<br />
board responds to its critics. Hastings <strong>Center</strong> Report<br />
32:27-33, 2002.<br />
2003<br />
Markovitz, BP and Goodman, KW. Case reports<br />
on the web redux: confidentiality still in jeopardy.<br />
Proceedings of the AMIA Annual Symposium<br />
926, 2003.<br />
W. JARRARD GOODWIN, M.D., F.A.C.S.<br />
Professor of Otolaryngology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Goodwin’s research focuses on the prevention<br />
and treatment of squamous cell carcinoma<br />
(SCCA) of the upper aerodigestive tract.<br />
<strong>Cancer</strong> Prevention and Control<br />
Dr. Goodwin has had a long-term interest in the<br />
potential of several micronutrients to inhibit the<br />
development of these cancers. Currently, various<br />
aspects of an extensive database from a phase III<br />
chemo-prevention trial, investigating the activity<br />
of beta-carotene, are being analyzed and published.<br />
He also is collaborating with investigators<br />
at the University of Florida on an NCI-funded<br />
oral cavity cancer control project. Disparities in<br />
mortality and stage at time of presentation for<br />
under-served populations is a developing interest.<br />
Quality of Life<br />
In addition, Dr. Goodwin studies the impact of<br />
treatment decisions on the quality of life experienced<br />
by patients with head and neck cancer.<br />
Current studies include collaborative investigations<br />
of speech and swallowing function following<br />
various treatment interventions. Working<br />
with Frank J. Penedo, Ph.D., he also is interested<br />
in the effect of stress and depression on survival<br />
and quality of life in this group of patients.<br />
Therapy<br />
Finally, Dr. Goodwin is actively involved in clinical<br />
trials studying the effect of P-53 gene therapy,<br />
alone and in combination with chemotherapy, for<br />
recurrent cancers of the oral cavity, pharynx, and<br />
larynx.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Civantos, FJ, Gomez, C, Duque, C, Pedroso, F,<br />
Goodwin, WJ, Weed, DT, Arnold, D, and<br />
Moffat, F. Sentinel node biopsy in oral cavity<br />
cancer: correlation with PET scan and immunohistochemistry.<br />
Head & Neck 25:1-9, 2003.<br />
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,<br />
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression<br />
of tumor markers hyaluronic acid and hyaluronidase<br />
(HYAL1) in head and neck tumors.<br />
International Journal of <strong>Cancer</strong> 106:438-45,<br />
2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Established, as one of the first investigators, the<br />
efficacy of selenium and retinoic acid in inhibiting<br />
carcinogenesis in an animal tumor model<br />
relevant to SCCA of the upper aerodigestive<br />
tract.<br />
• Published definitive outcomes studies analyzing<br />
the results of salvage treatment for recurrent<br />
cancer of the upper aerodigestive tract and for<br />
the treatment of Stage IV cancer.<br />
16<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
GAIL H. IRONSON, M.D., PH.D.<br />
Professor of Psychology<br />
DESCRIPTION OF RESEARCH<br />
Predictors of Long-Term Survivorship<br />
Dr. Ironson’s work focuses on identifying psychosocial<br />
characteristics of persons who become<br />
long-term survivors of HIV and cancer.<br />
Psychosocial Interventions to Improve<br />
Survivorship<br />
Parallel work by Dr. Ironson’s colleagues is evaluating<br />
the effects of interventions designed to<br />
boost emotional awareness and expression, build<br />
social support, and benefit breast cancer survivors<br />
and HIV-infected persons. This work is funded<br />
by two NIH/NIMH R01’s and an NCI P50.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,<br />
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,<br />
Schneiderman, N, and Fletcher, MA. Stress management<br />
and immune system reconstitution in<br />
symptomatic HIV-infected gay men over time:<br />
effects on transitional naive T cells<br />
(CD4(+)CD45RA(+)CD29(+)). American Journal<br />
of Psychiatry 159:143-5, 2002.<br />
Ironson, G, Freund, B, Strauss, JL, and Williams,<br />
J. Comparison of two treatments for traumatic<br />
stress: a community-based study of EMDR and<br />
prolonged exposure. Journal of Clinical Psychology<br />
58:113-28, 2002.<br />
Ironson, G, Solomon, GF, Balbin, EG,<br />
O’Cleirigh, C, George, A, Kumar, M, Larson, D,<br />
and Woods, TE. The Ironson-Woods Spirituality/<br />
Religiousness Index is associated with long survival,<br />
health behaviors, less distress, and low cortisol<br />
in people with HIV/AIDS. Annals of<br />
Behavioral Medicine 24:34-48, 2002.<br />
Freedland, KE, Skala, JA, Carney, RM,<br />
Raczynski, JM, Taylor, CB, Mendes De Leon,<br />
CF, Ironson, G, Youngblood, ME, Rama<br />
Krishnan, KR, and Veith, RC. The Depression<br />
Interview and Structured Hamilton (DISH): Rationale,<br />
development, characteristics, and clinical<br />
validity. Psychosomatic Medicine 64:897-905,<br />
2002.<br />
2003<br />
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,<br />
MA, Klimas, N, Duran, R, Ironson, G, and<br />
Schneiderman, N. Sleep disturbance mediates the<br />
association between psychological distress and<br />
immune status among HIV-positive men and<br />
women on combination antiretroviral therapy.<br />
Journal of Psychosomatic Research 54:185-9,<br />
2003.<br />
Lechner, SC, Antoni, MH, Lydston, D,<br />
LaPerriere, A, Ishii, M, Devieux, J, Stanley, H,<br />
Ironson, G, Schneiderman, N, Brondolo, E,<br />
Tobin, JN, and Weiss, S. Cognitive-behavioral<br />
interventions improve quality of life in women<br />
with AIDS. Journal of Psychosomatic Research<br />
54:253-61, 2003.<br />
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,<br />
MA, McGuffey, L, Balbin, E, Schneiderman, N,<br />
and Solomon, G. Emotional expression and<br />
depth processing of trauma and their relation to<br />
long-term survival in patients with HIV/AIDS.<br />
Journal of Psychosomatic Research 54:225-35,<br />
2003.<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, Fletcher, MA, and<br />
O’Sullivan, MJ. Stress as a predictor of symptomatic<br />
genital herpes virus recurrence in women<br />
with human immunodeficiency virus. Journal of<br />
Psychosomatic Research 54:237-44, 2003.<br />
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Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life<br />
stress and cervical squamous intraepithelial lesions<br />
in women with human papillomavirus and<br />
human immunodeficiency virus. Psychosomatic<br />
Medicine 65:427-34, 2003.<br />
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,<br />
Antoni, MH, Ironson, G, Malow, R, and<br />
Schneiderman, N. Coping and Psychological<br />
Distress Among Symptomatic HIV+ Men Who<br />
Have Sex With Men. Annals of Behavioral Medicine<br />
25:203-13, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Identified in her long-term survivorship studies<br />
a number of cognitive appraisal, emotional expression,<br />
and spiritual-related predictors that<br />
characterize HIV and cancer populations.<br />
• Used this information to relate these psychosocial<br />
characteristics to relevant physiological<br />
indicators (e.g., cortisol and natural killer cell<br />
toxicity (NKCC)) that may explain their association<br />
with extended survival and optimal<br />
health outcomes.<br />
ROBERT S. KIRSNER, M.D.<br />
Associate Professor of Dermatology and<br />
Cutaneous Surgery<br />
DESCRIPTION OF RESEARCH<br />
Dr. Kirsner’s research interests encompass skin<br />
cancer, health services research, and epidemiology.<br />
Specifically, he focuses on primary and<br />
secondary prevention of skin cancer. With regard<br />
to primary prevention efforts, his laboratory is<br />
evaluating the policies and procedures in the Miami-Dade<br />
County school system related to sun<br />
protection and studying the attitudes and behaviors<br />
of Hispanic students toward skin cancer prevention.<br />
His research will evaluate predictors of a<br />
school-based education program aimed at skin<br />
cancer education. Dr. Kirsner’s research efforts<br />
18<br />
regarding secondary prevention is aimed at determining<br />
prevalence of screening being performed<br />
in various settings, patient preferences regarding<br />
screening, and predictors of when skin cancer<br />
screening will occur. Dr. Kirsner’s work in health<br />
services research is aimed at determining the role<br />
of a health care delivery system for outcomes for<br />
skin cancer and other screenable cancers such as<br />
breast, colon, and cervical cancer. Researchers in<br />
this laboratory also are evaluating the effect of<br />
poverty and access to cancer-related services on<br />
cancer outcomes. Finally, Dr. Kirsner’s interest in<br />
epidemiology has focused on the role of ultraviolet<br />
light in the development and mortality of skin<br />
cancer and lymphoma.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Kirsner, RS , Fastenau, J, Falabella, A, Valencia, I,<br />
Long, R, and Eaglstein, WH. Clinical and economic<br />
outcomes with graftskin for hard-to-heal<br />
venous leg ulcers: a single-center experience. Dermatologic<br />
Surgery 28:81-82, 2002.<br />
Federman, DG, Kravetz, JD, and Kirsner, RS .<br />
Skin cancer screening by dermatologists: prevalence<br />
and barriers. Journal of the American Academy<br />
of Dermatology 46:710-14, 2002.<br />
Federman, DG and Kirsner, RS . The patient<br />
with skin disease: an approach for nondermatologists.<br />
Ostomy/Wound Management 48:22-8;<br />
quiz 29-30, 2002.<br />
Harrison-Balestra, C, Eaglstein, WH, Falabela,<br />
AF, and Kirsner, RS . Recombinant human platelet-derived<br />
growth factor for refractory nondiabetic<br />
ulcers: a retrospective series. Dermatologic<br />
Surgery 28:755-59; discussion 759-60, 2002.<br />
Sullivan, TP, Elgart, GW, and Kirsner, RS . Pemphigus<br />
and smoking. International Journal of<br />
Dermatology 41:528-30, 2002.<br />
Sullivan, TP and Kirsner, RS . Surgical pearl:<br />
punch technique to improve granulation over<br />
exposed tendons in chronic wounds. Journal of<br />
the American Academy of Dermatology 47:439-<br />
40, 2002.<br />
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Trent, JT and Kirsner, RS. Diagnosing necrotizing<br />
fasciitis. Advances In Skin & Wound Care<br />
15:135-38, 2002.<br />
Zacur, H and Kirsner, RS. Debridement: Rationale<br />
and Therapeutic Options. Wounds 14:2E-<br />
7E, 2002.<br />
2003<br />
Kirsner, R. New approaches to a timeless dilemma.<br />
Ostomy/Wound Management 49:12-14,<br />
2003.<br />
Li, J, Zhang, YP, and Kirsner, RS . Angiogenesis<br />
in wound repair: angiogenic growth factors and<br />
the extracellular matrix. Microscopy Research<br />
and Technique 60:107-14, 2003.<br />
Trent, JT, Kirsner, RS , Romanelli, P, and Kerdel,<br />
FA. Analysis of intravenous immunoglobulin for<br />
the treatment of toxic epidermal necrolysis using<br />
SCORTEN: The University of Miami Experience.<br />
Archives of Dermatology 139:39-43, 2003.<br />
Trent, JT and Kirsner, RS . Wounds and malignancy.<br />
Advances in Skin & Wound Care 16:31-<br />
34, 2003.<br />
Jacob, SE, Lodha, R, Cohen, JJ, Romanelli, P,<br />
and Kirsner, RS . Paraneoplastic eosinophilic<br />
fasciitis: a case report. Rheumatology International<br />
23:262-4, 2003.<br />
Martin, LK and Kirsner, RS . Ulcers caused by<br />
bullous morphea treated with tissue-engineered<br />
skin. International Journal of Dermatology<br />
42:402-04, 2003.<br />
Ayyalaraju, RS, Finlay, AY, Dykes, PJ, Trent, JT,<br />
Kirsner, RS , and Kerdel, FA. Hospitalization for<br />
severe skin disease improves quality of life in the<br />
United Kingdom and the United States: a comparative<br />
study. Journal of American Academy of<br />
Dermatology 49:249-54, 2003.<br />
Banta, MN, Eaglstein, WH, and Kirsner, RS .<br />
Healing of refractory sinus tracts by dermal matrix<br />
injection with Cymetra. Dermatologic Surgery<br />
29:863-66, 2003.<br />
Geren, SM, Kerdel, FA, Falabella, AF, Kirsner,<br />
RS. Infliximab: A treatment option for ulcerative<br />
pyoderma gangrenosum. Wounds 15:49-53,<br />
2003.<br />
Kirsner, RS . Infection and Intervention. Wounds<br />
15:127-28, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Found that differences in the stage of melanoma<br />
between patients enrolled in fee for<br />
service compared to HMO is related to patient<br />
access.<br />
• Described the correlation between melanoma<br />
in Black and Hispanic patients with UV exposure<br />
(the first to do so), suggesting a rationale<br />
of skin cancer prevention in darkly pigmented<br />
populations.<br />
• Established that a history of skin cancer is the<br />
most important predictor for determining<br />
whether a patient will have skin cancer screening<br />
performed by his primary care provider.<br />
MAHENDRA KUMAR, PH.D.<br />
Professor of Psychiatry and<br />
Behavioral Sciences<br />
DESCRIPTION OF RESEARCH<br />
Dr. Kumar is the director of the Molecular<br />
Neuroendocrinology and Neurotransmitters<br />
Laboratory in the department of Psychiatry and<br />
Behavioral Sciences at the University of Miami.<br />
He has been a close collaborator with Michael H.<br />
Antoni, Ph.D., Gail H. Ironson, M.D., Ph.D.,<br />
and Neil Schneiderman, Ph.D., over the past 15<br />
years in various research investigations including<br />
most recently, the <strong>Center</strong> for Psycho-Oncology<br />
Research (CPOR), funded by the NCI. Dr. Kumar<br />
conducts several neuroendocrinological protocols<br />
within the CPOR and is responsible for carrying<br />
out all the required assays to understand the mediating<br />
effects of stress hormones on health and<br />
immunological indices during cognitive-behavioral<br />
stress management (CBSM) intervention.<br />
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SELECTED PUBLICATIONS<br />
2002<br />
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,<br />
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,<br />
Schneiderman, N, and Fletcher, MA. Stress management<br />
and immune system reconstitution in<br />
symptomatic HIV-infected gay men over time:<br />
effects on transitional naive T cells<br />
(CD4(+)CD45RA(+)CD29(+)). American Journal<br />
of Psychiatry 159:143-5, 2002.<br />
Ironson, G, Solomon, GF, Balbin, EG,<br />
O’Cleirigh, C, George, A, Kumar, M, Larson, D,<br />
and Woods, TE. The Ironson-Woods Spirituality/<br />
Religiousness Index is associated with long survival,<br />
health behaviors, less distress, and low cortisol<br />
in people with HIV/AIDS. Annals of<br />
Behavioral Medicine 24:34-48, 2002.<br />
Kumar, M, Kumar, AM, Waldrop, D, Antoni,<br />
MH, Schneiderman, N, and Eisdorfer, C.<br />
The HPA axis in HIV-1 infection. Journal of<br />
Acquired Immune Deficiency Syndromes 31<br />
Supplement 2:S89-93, 2002<br />
2003<br />
Mitchell, A and Kumar, M. Psychological coping<br />
and cancer. Search strategy used is inadequate.<br />
British Medical Journal 326:598; author reply<br />
598, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Made available urinary, blood, and salivary cortisol<br />
measurements that help in the understanding<br />
of the acute and more enduring effects of<br />
this form of stress management on different<br />
cancer populations studied at UM/<strong>Sylvester</strong>.<br />
• Installed a real time polymerase chain reaction<br />
(PCR) facility, which has been used to quantify<br />
viral loads for HPV 16 and 18 sub-strains in<br />
HIV+ women at-risk for cervical neoplasia in<br />
one CPOR project. In fact, viral loads samples<br />
have been obtained from the participants.<br />
SUZANNE C. LECHNER, PH.D.<br />
Assistant Professor of Psychiatry and<br />
Behavioral Sciences<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lechner’s research in psycho-oncology<br />
focuses on two different themes: positive<br />
adaptation to breast cancer and the causes of late<br />
presentation to clinic following the detection of a<br />
breast cancer symptom. With regard to the first,<br />
Dr. Lechner is involved in clinical trials and correlational<br />
research studies to examine how people<br />
adjust to illness, and whether there are variables<br />
that can predict which patients will adapt well<br />
and which will require psychotherapeutic intervention.<br />
Within the context of all of these studies,<br />
she is interested in the complex relationships<br />
between positive adjustment and psychosocial<br />
and immunological/endocrine variables. The<br />
laboratory’s ongoing clinical intervention studies<br />
are examining the effects of a ten-week cognitivebehavioral<br />
stress management (CBSM) intervention<br />
versus a one-day stress management seminar<br />
on immunological, endocrine, and psychological<br />
outcomes for women with early stage breast cancer.<br />
In addition, Dr. Lechner is the primary investigator<br />
of another ongoing correlational research<br />
study, funded by the American Psychological Association<br />
Division 38, which will examine the<br />
correlates and consequences of benefit-finding<br />
(i.e., the belief that having cancer has led to positive<br />
life changes, such as better relationships with<br />
family and friends, a stronger sense of self-efficacy,<br />
and personal strength and redirected<br />
priorities).<br />
Dr. Lechner’s research also focuses on another<br />
topic: delayed presentation to clinic following<br />
the detection of a breast cancer symptom.<br />
Early detection and treatment has been shown to<br />
result in a significant reduction in breast cancer<br />
mortality. In spite of the importance of early detection,<br />
some women delay seeking consultation<br />
after they detect a suspicious breast cancer symp-<br />
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tom, such as a palpable breast lump or nipple<br />
discharge. Women who delay in seeking medical<br />
advice are more likely to present with advanced<br />
disease, thus limiting available treatment options<br />
and substantially impacting mortality. Previous<br />
studies have indicated that breast cancer patients<br />
who delayed as long as three to six months had<br />
poorer prognoses than those who sought treatment<br />
within three months of symptom detection.<br />
The reasons for delayed presentation are not well<br />
understood, but may include such factors as<br />
symptom-related information, sociodemographic<br />
variables, ethnicity-related factors (e.g., fatalism),<br />
attitudes and beliefs of the person’s social network<br />
or religion, psychological attributes, and knowledge-related<br />
factors. The percentage of women<br />
who present to the clinic with late stage breast<br />
cancer in the metropolitan Miami-Dade area is<br />
disproportionate to state and national averages,<br />
leading to the hypothesis that late presentation<br />
may be a significant health problem in this geographical<br />
area.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Lechner, SC, Antoni, MH, Lydston, D,<br />
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,<br />
Schneiderman, N, Brondolo, E, Tobin, J, and<br />
Weiss, S. Cognitive-behavioral interventions improve<br />
quality of life in women with AIDS. Journal<br />
of Psychosomatic Research 54:253-61, 2003.<br />
Lechner, SC, Zakowski, SG, Antoni, MH,<br />
Greenhawt, M, Block, K, and Block, P. Do<br />
sociodemographic and disease-related factors influence<br />
benefit-finding in cancer patients?<br />
Psycho-oncology 12:491-99, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
Development of Benefit-Finding in <strong>Cancer</strong><br />
Survivors<br />
One study examined patients’ perceptions that<br />
having cancer led to positive life changes, or<br />
benefit-finding, e.g., improved relationships,<br />
enhanced appreciation of life, increased resilience,<br />
and self-reliance. The laboratory investigated<br />
the relationship between benefit-finding and<br />
sociodemographic (e.g., gender, age, marital<br />
status, education, and income) and diseaserelated<br />
variables (e.g., severity of disease, or<br />
cancer stage, or time since diagnosis).<br />
• As hypothesized, benefit-finding was greater in<br />
younger patients, and also differed by stage of<br />
disease in a curvilinear fashion. Individuals with<br />
Stage II disease had significantly higher benefitfinding<br />
scores than those with Stage IV or Stage<br />
I cancer.<br />
• Time since diagnosis and treatment status<br />
(i.e., currently in treatment, completed treatment,<br />
or no treatment) were not related to<br />
benefit-finding.<br />
• Findings suggest that stage of disease is an important<br />
factor to consider when investigating<br />
positive perceptions of disease in individuals<br />
with cancer.<br />
Another study examined whether various<br />
measures of positive thinking (i.e., Life Orientation<br />
Test-Revised for Optimism) and found<br />
meaning (Benefit-Finding Scale) measured over a<br />
one-year period following surgery for early stage<br />
breast cancer were associated with adjustment<br />
(i.e., Profile of Mood States, Quality of Life<br />
(QOL), and CES-Depression).<br />
• Controlling for baseline levels of adjustment,<br />
greater optimism at one-year follow-up was associated<br />
with concurrent higher vigor, better<br />
QOL, fewer depressive symptoms, less anxiety,<br />
depression, anger, and fatigue.<br />
• One-year follow-up benefit-finding was correlated<br />
with concurrent higher vigor, better QOL,<br />
fewer depressive symptoms, and less anxiety<br />
when baseline adjustment scores were controlled.<br />
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• Findings suggest that maintaining a positive<br />
attitude may relate to psychological well-being<br />
over the year post surgery.<br />
An additional study revealed that there were<br />
complex relationships between benefit-finding<br />
and coping over the one-year period following<br />
surgery for early stage breast cancer.<br />
• During the early period of dealing with the diagnosis<br />
of and treatment for breast cancer, for<br />
example, benefit-finding is associated with<br />
greater positive reframing, religious coping, selfdistraction,<br />
substance use, examining emotions,<br />
and seeking less social support. By mid-treatment<br />
(three months later), active coping and<br />
religious coping were important correlates of<br />
benefit-finding, while after treatment completion<br />
(six months), higher benefit-finding was<br />
related to greater active coping, examining emotions,<br />
seeking social support, religious coping,<br />
and reduced use of acceptance coping. However,<br />
by one year after surgery, greater benefitfinding<br />
was associated with using positive<br />
reframing and planning coping strategies.<br />
• Thus, effective coping strategies early on may be<br />
those that help women modulate their emotions<br />
and maintain hope. Later on, the most<br />
effective strategies appear to be those that help<br />
them move on and plan for the future.<br />
• The research outcome suggests that finding<br />
benefits in cancer may be differentially related<br />
to the coping strategies women employ at different<br />
points during the treatment trajectory,<br />
which may have important implications for tailoring<br />
psychosocial interventions across medical<br />
treatment.<br />
DAVID J. LEE, PH.D.<br />
Associate Professor of Epidemiology and<br />
Public Health<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lee is a chronic disease epidemiologist<br />
with a long-standing interest in the prevalence<br />
of, and morbidities associated with, sensory-related<br />
diseases and impairments. In the past<br />
two years, he has published findings that examined<br />
cancer mortality risk in community-residing<br />
adults with visual impairment and glaucoma. Previous<br />
research has suggested an association between<br />
cancer risk and eye disease. Dr. Lee and his<br />
colleagues found, however, that detection bias, in<br />
part, might be responsible for this association.<br />
Their findings were of sufficient merit to warrant<br />
publication of an accompanying editorial by a<br />
leading ophthalmic epidemiologist.<br />
Dr. Lee entered the field of tobacco control<br />
research in 2000, where he now devotes 60 percent<br />
of his research efforts. Since this career shift,<br />
he has served as co-investigator of the Florida<br />
Youth Cohort Study that is following a sample of<br />
Florida adolescents in order to monitor changes<br />
in tobacco-related attitudes/beliefs and behaviors.<br />
He also is the lead author on three papers reporting<br />
results from this work. Dr. Lee also is the<br />
principal investigator of two Flight Attendant<br />
Medical Research Institute (FAMRI)-funded<br />
grants to study the influence of second-hand<br />
smoke on the health of adolescents. Using<br />
UM/<strong>Sylvester</strong> developmental funds, Dr. Lee<br />
fielded a school-based pilot study in <strong>2004</strong> that<br />
examined second-hand smoke exposure and cancer<br />
risk factors in an ethnically diverse group of<br />
middle-school students. Findings from this study<br />
will be used to develop an intervention designed<br />
to reduce cancer risk factors in this population.<br />
It will be submitted for possible funding to the<br />
NCI in February 2005.<br />
22<br />
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Dr. Lee also has developed an interest in the<br />
identification of cancer risk factors in adults. For<br />
example, he recently co-authored a paper examining<br />
cancer mortality risk in pesticide applicators.<br />
He served as the dissertation chair for a project<br />
examining cancer risk in Florida firefighters. Two<br />
papers examining cancer mortality and cancer<br />
incidence in this occupational group are presently<br />
under peer review. In 2003, Dr. Lee and his colleagues<br />
published a lead article in the journal<br />
Ophthalmology examining the association between<br />
glaucoma and cause-specific mortality including<br />
cancer. Dr. Lee’s most recent tobacco-related<br />
publication focused on trends in smoking rates<br />
among 209 of the largest worker groups in the<br />
United States. This paper was published in the<br />
Journal of Occupational and Environmental<br />
Medicine in <strong>2004</strong>.<br />
A novel non-nicotine replacement therapy<br />
smoking cessation strategy for older adults with<br />
chronic disease, including cancer patients, is<br />
presently under review by the NCI. A cognitive<br />
behavioral smoking cessation program directed<br />
at military recruits prior to entry into basic<br />
training is also under review at the Department<br />
of Defense.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lee, DJ, Gomez-Marin, O, Lam, BL, and Zheng,<br />
DD. Visual acuity impairment and mortality in<br />
U.S. adults. Archives of Ophthalmology<br />
120:1544-50, 2002.<br />
Lee, DJ, Trapido, E, and Rodriguez, R. Self-reported<br />
school difficulties and tobacco use among<br />
fourth- to seventh-grade students. Journal of<br />
School Health 72:368-73, 2002.<br />
2003<br />
Fleming, LE, Gomez-Marin, O, Zheng, D, Ma,<br />
F, and Lee, DJ. National Health Interview Survey<br />
mortality among U.S. farmers and pesticide<br />
applicators. American Journal of Industrial<br />
Medicine 43:227-33, 2003.<br />
Lee, DJ, Gomez-Marin, O, Ma, F, and Lam, BL.<br />
Uncorrected binocular distance visual acuity<br />
impairment and survival: The National Health<br />
and Nutrition Examination Survey I. Ethnicity<br />
and Disease 13:485-91, 2003.<br />
Lee, DJ, Trapido, E, and Rodriguez, R. Secondhand<br />
smoke and earaches in adolescents: The<br />
Florida Youth Cohort Study. Nicotine and Tobacco<br />
Research 5:1-4, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated an association between exposure<br />
to second-hand smoke and self-reported earaches<br />
in adolescents, which is novel in that<br />
these associations have typically been reported<br />
in younger children and infants. The two<br />
FAMRI-funded studies will help to determine if<br />
biologically confirmed exposure to second-hand<br />
smoke is related to both reported earaches and<br />
clinically confirmed indicators of middle ear<br />
problems.<br />
SILVINA LEVIS-DUSSEAU, M.D.<br />
Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
For the last ten years, Dr. Levis-Dusseau, director<br />
of the Osteoporosis <strong>Center</strong>, a joint venture<br />
between the University of Miami School of<br />
Medicine and the Miami Veterans Administration<br />
Medical <strong>Center</strong>, has been conducting clinical<br />
trials testing the effectiveness of different drugs in<br />
the treatment of osteoporosis. Currently, she is<br />
conducting an NIH-sponsored trial that will<br />
evaluate the effectiveness of estrogens derived<br />
from soy in preventing menopausal symptoms<br />
and bone loss. Her research interests also include<br />
improving muscle function and bone mass in<br />
elderly individuals with vitamin D deficiency.<br />
Dr. Levis-Dusseau has collaborated with Bernard<br />
A. Roos, M.D., Michael H. Antoni, Ph.D., and<br />
Neil Schneiderman, Ph.D., for the past three<br />
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years to conduct a clinical trial testing the effects<br />
of low-dose estrogen treatment on quality of life,<br />
osteoporosis risk, and other physical indicators in<br />
men who had undergone androgen deprivation<br />
therapy for metastatic prostate cancer. This<br />
project is funded by the NCI as part of the<br />
<strong>Center</strong> for Psycho-Oncology Research (CPOR),<br />
which is directed by Michael H. Antoni, Ph.D.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Levis, S, Quandt, SA, Thompson, D, Scott, J,<br />
Schneider, DL, Ross, PD, Black, D, Suryawanshi,<br />
S, Hochberg, M, and Yates, J. Alendronate reduces<br />
the risk of multiple symptomatic fractures:<br />
results from the fracture intervention trial. Journal<br />
of the American Geriatric Society 50:409-15,<br />
2002.<br />
2003<br />
Hernandez-Cassis, C, Vogel, CK, Hernandez, TP,<br />
Econs, MJ, Iglesias, M, Iglesias, A, Levis, S,<br />
Roos, BA, Howard, GA, and Gamarra, AI. Autosomal<br />
dominant hyperostosis/osteosclerosis with<br />
high serum alkaline phosphatase activity. Journal<br />
of Clinical Endocrinology & Metabolism<br />
88:2650-55, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Discovered that vitamin D deficiency in South<br />
Florida residents is higher than expected: approximately<br />
25 percent in young adults and 30<br />
percent in the elderly.<br />
FRANK J. PENEDO, PH.D.<br />
Assistant Professor of Psychology<br />
Psycho-Oncology, Psychology of Aging and<br />
Immunosenescence in Chronically Ill Older<br />
Adults<br />
Within the fields of health psychology and behavioral<br />
medicine, cancer and the human immunodeficiency<br />
virus (HIV) have provided unique<br />
opportunities to evaluate the role of psychosocial<br />
factors in disease acquisition and progression<br />
among various populations. Part of Dr. Penedo’s<br />
research is examining the role of psychosocial factors<br />
such as stress, coping, and personality style in<br />
psychological distress and physical health status<br />
in three specific populations: 1) HIV+ ethnically<br />
diverse men who have sex with men (MSM) and<br />
heterosexual older men with a history of substance<br />
use, 2) men treated with radical prostatectomy<br />
or radiation for localized prostate cancer,<br />
and 3) men and women diagnosed with Stages I-<br />
III of head and neck cancer.<br />
Dr. Penedo’s research with these chronic disease<br />
groups is focused primarily on evaluating the<br />
efficacy of group- and individual-based stress<br />
management interventions on reducing distress<br />
and improving quality of life (QOL) and physical<br />
health status among older cancer or HIV populations<br />
(50 years and older). Dr. Penedo is particularly<br />
interested in how psychosocial factors such<br />
as stress, coping, and personality style may interact<br />
with health behaviors (e.g., treatment adherence),<br />
neuroendocrine function, and the agerelated<br />
decrements in immune function (i.e.,<br />
immuno-senescence) seen in older populations.<br />
More specifically, he is interested in how stress<br />
and other psychosocial factors may interact with,<br />
and exacerbate, age-related decrements in immune<br />
function on the one hand, and disease<br />
progression in older cancer and HIV populations<br />
on the other.<br />
Several of the research questions involved in<br />
Dr. Penedo’s work aim to answer: 1) whether psychosocial<br />
factors impact neuroendocrine and immune<br />
parameters in chronically ill older adults<br />
(e.g., Does psychological stress-related activation<br />
24<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
of the HPAC-axis lead to suppressed immunity,<br />
particularly shifts in specific T-cell and cytokine<br />
subpopulations and angiogenic factors?), 2) the<br />
extent to which age-related decrements in immunity<br />
can be exacerbated (or buffered) by psychosocial<br />
factors (e.g., Are there protective<br />
psychosocial factors such as coping repertoires or<br />
personality styles that may buffer the effects of<br />
distress on immune function or age-related decrements<br />
in immunity? Can psychosocial interventions<br />
modify these factors in an aim to sustain or<br />
enhance immunity as well as ameliorate disease<br />
progression?), and 3) the clinical implication of<br />
the impact of psychosocial factors on neuroendocrine<br />
and immune function in older chronically<br />
ill populations (e.g., What is the clinical significance—disease<br />
progression, improved physical<br />
health status—of the relationship between<br />
psychosocial factors and neuroendocrine and<br />
immune function in older adults?).<br />
In an effort to answer these questions,<br />
Dr. Penedo is involved in several biopsychosocial<br />
HIV and cancer studies evaluating the role of<br />
psychosocial factors and psychosocial interventions<br />
on QOL, immune function, and health<br />
status.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,<br />
Carver, CS, Antoni, MH, Roos, BA, and<br />
Schneiderman, N. Perceived stress management<br />
skill mediates the relationship between optimism<br />
and positive mood following radical prostatectomy.<br />
Health Psychology 22:220-22, 2003.<br />
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, M,<br />
Malow, R, Costa, P, and Schneiderman, N. Personality,<br />
quality of life and HAART adherence<br />
among men and women living with HIV/AIDS.<br />
Journal of Psychosomatic Research 54:271-78,<br />
2003.<br />
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,<br />
Antoni, MH, Ironson, G, Malow, R, and<br />
Schneiderman, N. Coping and psychological distress<br />
among symptomatic HIV+ men who have<br />
sex with men. Annals of Behavioral Medicine<br />
25:203-13, 2003.<br />
BERNARD A. ROOS, M.D.<br />
Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Roos’ current clinical research involves<br />
adult stem cells as well as hormone and exercise<br />
therapy in men and women, particularly frail<br />
elderly. One project is directed at the role of estrogen<br />
in the aging male and the other on the<br />
restorative effects of resistance exercise in frail<br />
elderly. In addition, there are several major research<br />
and training initiatives in geriatrics.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Yang, ES, Maiorino, CA, Roos, BA, Knight, SR,<br />
and Burnstein, KL. Vitamin-D mediated growth<br />
inhibition of an androgen-ablated LNCaP cell<br />
line model of human prostate cancer. Molecular<br />
and Cellular Endocrinology 186:69–79, 2002.<br />
D’Ippolito, G, Schiller, PC, Balkan, W, Roos,<br />
BA, and Howard, GA. Cooperative anabolic actions<br />
of HGF and 1,25-dihydroxyvitamin D 3<br />
in<br />
osteoblastic differentiation of human vertebral<br />
marrow stromal fibroblasts. Bone 31:269–75,<br />
2002.<br />
Perez-Stable, CM, Schwartz, GG, Farinas, A,<br />
Finegold, M, Binderup, L, Howard, GA, and<br />
Roos, BA. The Gγ/T-15 transgenic mouse model<br />
of androgen-independent prostate cancer: target<br />
cells of carcinogenesis and the effect of the vitamin<br />
D analog EB 1089. <strong>Cancer</strong> Epidemiology,<br />
Biomarkers and Prevention 1555–63, 2002.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 25
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
Signorile, JF, Carmel, MP, Czaja, SJ, Asfour, SS,<br />
Morgan, RO, Khalil, TM, Ma, F, and Roos, BA.<br />
Differential increases in average isokinetic power<br />
by specific muscle groups of older women due to<br />
variations in training and testing. Journal of Gerontology:<br />
Medical Sciences 57:M683–M690,<br />
2002.<br />
Signorile, JF and Roos, BA. Resistance training<br />
for power, strength, and functionality: a longterm<br />
prescription. American Journal of the Medical<br />
Sciences 398-402, September/October, 2002.<br />
2003<br />
Hernandez-Cassis, C, Vogel, CK, Hernandez, TP,<br />
Econs, MJ, Iglesias, M, Iglesias, A, Levis, S,<br />
Roos, BA, Howard, GA, and Gamarra, AI. Autosomal<br />
dominant hyperostosis/osteosclerosis with<br />
high serum alkaline phosphatase activity. Journal<br />
of Clinical Endocrinology & Metabolism<br />
88:2650-55, 2003.<br />
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,<br />
Carver, CS, Antoni, MH, Roos, BA, and<br />
Schneiderman, N. Perceived stress management<br />
skill mediates the relationship between optimism<br />
and positive mood following radical prostatectomy.<br />
Health Psychology 22:220-22, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• The laboratory’s research on exercise and nutrition<br />
continues to improve the prescription of<br />
exercise and nutrition in the frail and vulnerable<br />
elderly. They have completed preliminary studies<br />
of a speed-training method to improve mobility<br />
that revealed a special role for neural<br />
coordination. Important physical function correlates<br />
with vitamin deficiency, and a clinical<br />
trial has demonstrated the effects of correcting<br />
vitamin deficiency on the mobility of older<br />
persons.<br />
• Osteoporosis therapy approaches have emerged<br />
from studies of normal human stem cells and<br />
studies of artificial matrix that can support their<br />
growth and mineralization. Researchers in Dr.<br />
Roos’ laboratory have discovered a unique combination<br />
of matrix, hormones, vitamins, and<br />
growth factors that promotes the maturation<br />
and growth of stem cells that forms bone in tissue<br />
culture and in animal transplants. Tissue<br />
engineering approaches also are being examined<br />
as they address the many safety issues that will<br />
ultimately allow the application of these new<br />
technologies to persons with osteoporosis.<br />
• Hormonal changes in aging individuals continue<br />
to offer the opportunity—through hormone<br />
replacement therapy—to slow the aging<br />
process. Following up on earlier studies of sex<br />
hormone deficiency and concerns over the<br />
many diverse complications of sex hormone<br />
replacement, researchers in this laboratory have<br />
begun to evaluate various nutritional supplements<br />
such as soy protein chemicals that can act<br />
as sex hormone replacements without causing<br />
increased risk of cancer. Moreover, the initial<br />
studies of vitamins in aging persons have been<br />
completed, reporting that 20 percent of older<br />
ambulatory South Floridians are vitamin D<br />
deficient. Planning for several studies to assess<br />
the dose and effects of successful vitamin D<br />
replacement in older persons is underway. The<br />
initial focus is on benefits of vitamin D replacement<br />
on gait, balance, and other mobilityrelated<br />
factors.<br />
• New hormonal interventions that can improve<br />
the mood of men undergoing hormone-deprivation<br />
therapy for advancing prostate cancer are<br />
now being examined. The laboratory, through<br />
an NCI-funded study, will aim to demonstrate<br />
that low-dose estrogen replacement might benefit<br />
men with prostate cancer. Similar studies<br />
based on the use of estrogen-like nutritional<br />
compounds, such as soy isoflavones, also are<br />
being considered.<br />
26<br />
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C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
NEIL SCHNEIDERMAN, PH.D.<br />
Professor of Psychology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Schneiderman’s research focuses on improving<br />
the quality of life (QOL) in men<br />
who have undergone radical prostatectomy or<br />
beam radiation treatment for localized prostate<br />
cancer. As project leader of a study titled “Cognitive-Behavioral<br />
Stress Management and Prostate<br />
<strong>Cancer</strong>” on <strong>Center</strong> Grant P50 CA84944 (under<br />
Michael H. Antoni Ph.D.’s direction as principal<br />
investigator), Dr. Schneiderman’s laboratory is<br />
conducting studies comparing a ten-week cognitive-behavioral<br />
stress management (CBSM)<br />
program versus a one-day CBSM seminar. They<br />
are examining QOL indicators and immune<br />
system status (e.g., natural killer cell cytotoxicity<br />
(NKCC)) throughout a 12-month follow-up<br />
period.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,<br />
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,<br />
Schneiderman, N, and Fletcher, MA. Stress management<br />
and immune system reconstitution in<br />
symptomatic HIV-infected gay men over time:<br />
effects on transitional naive T cells<br />
(CD4(+)CD45RA(+)CD29(+)). American Journal<br />
of Psychiatry 159:143-45, 2002.<br />
Kumar, M, Kumar, AM, Waldrop, D, Antoni,<br />
MH, Schneiderman, N, and Eisdorfer, C.<br />
The HPA axis in HIV-1 infection. Journal of<br />
Acquired Immune Deficiency Syndromes 31<br />
(Supplement 2):S89-93, 2002.<br />
Williams, R, Schneiderman, N, Relman, A, and<br />
Angell, M. Resolved: psychosocial interventions<br />
can improve clinical outcomes in organic disease—rebuttals<br />
and closing arguments. Psychosomatic<br />
Medicine 64:564-67, 2002.<br />
Williams, RB and Schneiderman, N. Resolved:<br />
psychosocial interventions can improve clinical<br />
outcomes in organic disease (pro). Psychosomatic<br />
Medicine 64:552-57, 2002.<br />
Kline, KA, Saab, PG, Llabre, MM, Spitzer, SB,<br />
Evans, JD, McDonald, PA, and Schneiderman,<br />
N. Hemodynamic response patterns: responder<br />
type differences in reactivity and recovery. Psychophysiology<br />
39:739-46, 2002.<br />
2003<br />
Perna, FM, Antoni, MH, Baum, A, Gordon, P,<br />
and Schneiderman, N. Cognitive behavioral<br />
stress management effects on injury and illness<br />
among competitive athletes: a randomized clinical<br />
trial. Annals of Behavioral Medicine 25:66-<br />
73, 2003.<br />
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,<br />
MA, Klimas, N, Duran, R, Ironson, G, and<br />
Schneiderman, N. Sleep disturbance mediates<br />
the association between psychological distress and<br />
immune status among HIV-positive men and<br />
women on combination antiretroviral therapy.<br />
Journal of Psychosomatic Research 54:185-89,<br />
2003.<br />
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,<br />
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,<br />
and Schneiderman, N. Psychological distress is<br />
associated with decreased memory helper T cell<br />
and B cell counts in pre-AIDS HIV seropositive<br />
men and women but only in those with low viral<br />
load. Psychosomatic Medicine 65:627-35, 2003.<br />
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,<br />
MA, McGuffey, L, Balbin, E, Schneiderman, N,<br />
and Solomon, G. Emotional expression and<br />
depth processing of trauma and their relation to<br />
long-term survival in patients with HIV/AIDS.<br />
Journal of Psychosomatic Research 54:225-35,<br />
2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 27
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
Lechner, SC, Antoni, MH, Lydston, D,<br />
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,<br />
Schneiderman, N, Brondolo, E, Tobin, J, and<br />
Weiss, S. Cognitive-behavioral interventions improve<br />
quality of life in women with AIDS. Journal<br />
of Psychosomatic Research 54:253-61, 2003.<br />
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, M,<br />
Malow, R, Costa, P, and Schneiderman, N. Personality,<br />
quality of life and HAART adherence<br />
among men and women living with HIV/AIDS.<br />
Journal of Psychosomatic Research 54:271-78,<br />
2003.<br />
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,<br />
Antoni, MH, Ironson, G, Malow, R, and<br />
Schneiderman, N. Coping and psychological distress<br />
among symptomatic HIV+ men who have<br />
sex with men. Annals of Behavioral Medicine<br />
25:203-13, 2003.<br />
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,<br />
Carver, CS, Antoni, MH, Roos, BA, and<br />
Schneiderman, N. Perceived stress management<br />
skill mediates the relationship between optimism<br />
and positive mood following radical prostatectomy.<br />
Health Psychology 22:220-22, 2003.<br />
Berkman, LF, Blumenthal, J, Burg, M, Carney,<br />
RM, Catellier, D, Cowan, MJ, Czajkowski, SM,<br />
DeBusk, R, Hosking, J, Jaffe, A, Kaufmann, PG,<br />
Mitchell, P, Norman, J, Powell, LH, Raczynski,<br />
JM, and Schneiderman, N. Enhancing Recovery<br />
in Coronary Heart Disease Patients Investigators<br />
(ENRICHD). Effects of treating depression and<br />
low perceived social support on clinical events<br />
after myocardial infarction: the Enhancing Recovery<br />
in Coronary Heart Disease Patients<br />
(ENRICHD) Randomized Trial. Journal of the<br />
American Medical Association 289:3106-16,<br />
2003.<br />
Watkins, LL, Schneiderman, N, Blumenthal, JA,<br />
Sheps, DS, Catellier, D, Taylor, CB, and<br />
Freedland, KE; ENRICHD Investigators. Cognitive<br />
and somatic symptoms of depression are associated<br />
with medical comorbidity in patients<br />
after acute myocardial infarction. American Heart<br />
Journal 146:48-54, 2003.<br />
Fernander, AF, Durán, REF, Saab, PG, Llabre,<br />
MM, and Schneiderman, N. Assessing the reliability<br />
and validity of the John Henry Active<br />
Coping Scale in an urban sample of African<br />
Americans and White Americans. Ethnicity &<br />
Health 8:147-61, 2003.<br />
Kline, KA, Saab, PG, Llabre, MM, Spitzer, SB,<br />
Evans, JD, McDonald, PAG, and Schneiderman,<br />
N. Hemodynamic response patterns: Responder<br />
type differences in reactivity and recovery. Psychophysiology<br />
39:739-46, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Maintaining an optimistic outlook is associated<br />
with greater NKCC by way of greater emotional<br />
expression.<br />
• Perceived stress management skills mediate<br />
improvements in mood and QOL during the<br />
CBSM intervention.<br />
• Intervention-related gains in QOL may be<br />
paralleled by gonadal hormone (testosterone)<br />
changes.<br />
GAIL S. SHOR-POSNER, PH.D.<br />
Professor of Psychiatry and Behavioral<br />
Sciences<br />
DESCRIPTION OF RESEARCH<br />
Dr. Shor-Posner is funded by the NCI as part<br />
of the Women’s Intervention Nutrition<br />
Study (WINS). She received this funding for the<br />
Low Fat Diet and Breast <strong>Cancer</strong> Recurrence/Outcome<br />
Trial. The goal of this multi-site project is<br />
to determine whether a program of dietary fat<br />
intake reduction, provided in addition to defined<br />
adjuvant therapy, will effectively prolong diseasefree<br />
survival for patients between 48 and 78 years<br />
of age with early stage breast cancer. The study is<br />
ongoing, and a proposal has been submitted for<br />
continuation until 2007.<br />
28<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
Dr. Shor-Posner is the principal investigator<br />
of the Fogarty International <strong>Center</strong> (FIC) AIDS<br />
and TB International Training and Research Program,<br />
funded by the NIH/FIC. The AIDS training<br />
curriculum is an international program<br />
designed to contribute to research capacity building<br />
in targeted developing countries, to facilitate<br />
the ability of scientists/clinicians to slow HIV-1<br />
disease progression, prevent maternal-to-child<br />
transmission, and enhance survival. This program<br />
also seeks to provide training to qualified health<br />
professionals from two countries that are currently<br />
experiencing the most dramatic increases<br />
in TB and multi-drug resistant TB (MDR-TB)<br />
in the Americas, Honduras, and the Dominican<br />
Republic.<br />
Dr. Shor-Posner also is the mentor of Florida<br />
Department of Health-funded research titled,<br />
“Pulmonary Complications in Tobacco Users Infected<br />
With the Human Immunodeficiency Virus:<br />
Therapeutic Implications.” This proposal is<br />
for evaluation of the frequency of tobacco use<br />
among HIV+ individuals hospitalized at Jackson<br />
Memorial Hospital and the impact of tobacco use<br />
on the risk of developing lower respiratory infections.<br />
Additionally, Dr. Shor-Posner is the nutrition<br />
director of the NIH-funded General Clinical<br />
Research <strong>Center</strong> (GCRC). The GCRC, while<br />
located in several locations, functions as a single<br />
integrated department/unit with single program<br />
leadership and coordination. This clinical research<br />
infrastructure provides a conduit for the<br />
enhancement of multi-specialty projects.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Miguez-Burbano, MJ, Pineda-Medina, L,<br />
Lecusay, R, Page, JB, Castillo, G, Burban, X,<br />
Rodriguez, A, Rodriguez, N, and Shor-Posner,<br />
G. Continued high risk behaviors in HIV infected<br />
drug abusers. Journal of Addictive Diseases<br />
21:67-80, 2002.<br />
Shor-Posner, G , Miguez, MJ, Pineda, LM,<br />
Rodriguez, A, Ruiz, P, Castillo, G, Burban, X,<br />
Lecusay, R, and Baum, M. Impact of selenium<br />
status on the pathogenesis of mycobacterial disease<br />
in HIV-1-infected drug users during the era<br />
of highly active antiretroviral therapy. Journal of<br />
Acquired Immune Deficiency Syndromes<br />
29:169-73, 2002.<br />
Miguez-Burbano, MJ, Burbano, X, Rodriguez, A,<br />
Lecusay, R, Rodriguez, N, and Shor-Posner, G .<br />
Development of thrombocytosis in HIV+ drug<br />
users: impact of antiretroviral therapy. Platelets<br />
13:183-85, 2002.<br />
Miguez, MJ, Burbano, X, Archer, H, and<br />
Shor-Posner, G . Limited impact of highly active<br />
antiretroviral therapy in thrombocytopenia.<br />
Journal of Acquired Immune Deficiency<br />
Syndromes 30:260-61, 2002.<br />
Miguez-Burbano, MJ, Navas, R, Forero, MG,<br />
Burbano, X, Rodriguez, N, and Shor-Posner, G .<br />
Evaluation of HIV prevention and counseling<br />
practices of obstetrician/gynecologists in Bogota,<br />
Colombia: impact on women’s knowledge and<br />
risk practices. AIDS Education and Prevention<br />
14:72-80, 2002.<br />
Shor-Posner, G , Lecusay, R, Morales, G, Campa,<br />
A, and Miguez-Burbano, MJ. Neuroprotection in<br />
HIV-positive drug users: implications for antioxidant<br />
therapy. Journal of Acquired Immune Deficiency<br />
Syndromes 31 Supplement 2:S84-88,<br />
2002.<br />
Burbano, X, Miguez-Burbano, MJ, McCollister,<br />
K, Zhang, G, Rodriguez, A, Ruiz, P, Lecusay, R,<br />
and Shor-Posner, G . Impact of a selenium<br />
chemoprevention clinical trial on hospital admissions<br />
of HIV-infected participants. HIV Clinical<br />
Trials 3:483-91, 2002.<br />
Shor-Posner, G , Lecusay, R, Miguez-Burbano,<br />
MJ, Morales, G, and Campa, A. Neuroprotection<br />
in HIV+ drug users: implications for antioxidant<br />
therapy. Journal of Acquired Immune Deficiency<br />
Syndromes 31:S84-S88, 2002.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 29
C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
2003<br />
Miguez-Burbano, MJ, Archer, H, Rodriguez, M,<br />
and Shor-Posner, G . Discontinuation of secondary<br />
prophylaxis and the risk of Pneumocystis<br />
carinii pneumonia. AIDS 17:140-41, 2003.<br />
Shor-Posner, G , Lecusay, R, Miguez, MJ,<br />
Moreno-Black, G, Zhang, G, Rodriguez, N,<br />
Burbano, X, Baum, M, and Wilkie, F. Psychological<br />
burden in the era of HAART: impact of<br />
selenium therapy. International Journal of Psychiatry<br />
in Medicine 33:55-69, 2003.<br />
Miguez, MJ, Shor-Posner, G , Morales, G,<br />
Rodriguez, A, and Burbano, X. HIV treatment in<br />
drug abusers: impact of alcohol use. Addiction<br />
Biology 8:33-37, 2003.<br />
Miguez-Burbano, MJ, Burbano, X, Ashkin, D,<br />
Pitchenik, A, Allan, R, Pineda, L, Rodriguez, N,<br />
and Shor-Posner, G . Impact of tobacco use on<br />
the development of opportunistic respiratory<br />
infections in HIV seropositive patients on<br />
antiretroviral therapy. Addiction Biology<br />
8:39-43, 2003.<br />
Perez-Then, E, Peña, R, Tavarez-Roja, M, Peña,<br />
C, Quiñonez, S, Buttler, M, Ammann, A,<br />
Hernandez, W, Goyanes, M, Miguez, MJ, Shor-<br />
Posner, G, and PMTCT Group. Preventing<br />
mother-to-child HIV transmission in a developing<br />
country: the Dominican Republic experience.<br />
Journal of Acquired Immune Deficiency Syndromes<br />
34:506-11, 2003.<br />
LEO B. TWIGGS, M.D.<br />
Professor and Associate Dean of Women’s<br />
Health, Interim Chairman of Obstetrics and<br />
Gynecology, and Medical Director, Institute<br />
for Women’s Health<br />
DESCRIPTION OF RESEARCH<br />
Dr. Twiggs, who also is the Dean of Women’s<br />
Health at the University of Miami School of<br />
Medicine, has tested the efficacy of a vaccine for<br />
human papillomavirus (HPV) as a method of<br />
controlling the risk of cervical cancer. He also<br />
collaborates with Michael H. Antoni, Ph.D., and<br />
Mary Josephine O’Sullivan, M.D., to conduct<br />
studies of the effects of stressors and stress management<br />
on health behaviors and cervical neoplasia<br />
in women co-infected with HIV and HPV.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Wright, TC Jr., Cox, JT, Massad, LS, Twiggs,<br />
LB, and Wilkinson, EJ. ASCCP-Sponsored Consensus<br />
Conference. 2001 Consensus Guidelines<br />
for the management of women with cervical cytological<br />
abnormalities. Journal of the American<br />
Medical Association 287:2120-29, 2002.<br />
2003<br />
Wright, TC Jr., Cox, JT, Massad, LS, Carlson, J,<br />
Twiggs, LB , and Wilkinson, EJ. American Society<br />
for Colposcopy and Cervical Pathology 2001<br />
consensus guidelines for the management of<br />
women with cervical intraepithelial neoplasia.<br />
American Journal of Obstetrics and Gynecology<br />
189:295-304, 2003.<br />
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C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M<br />
HIGHLIGHTS/DISCOVERIES<br />
• <strong>Cancer</strong> control research—The Institute for<br />
Women’s Health has an active cancer control<br />
research program. Dr. Twiggs, Timothy De<br />
Santis, M.D., and Nahida Chakhtoura, M.D.,<br />
have been collaborating with two medical device<br />
companies utilizing spectroscopic measures<br />
in cervical precursors in an effort to diagnose<br />
and prevent cervical cancer. This collaboration<br />
in an Institutional Review Board (IRB)-<br />
approved research setting resulted in the<br />
evaluation of more than 300 women with<br />
abnormal Pap smears in three separate clinical<br />
research protocols.<br />
JAMES D. WILKINSON, M.D., M.P.H.<br />
Associate Professor of Epidemiology and<br />
Public Health<br />
DESCRIPTION OF RESEARCH<br />
Dr. Wilkinson’s research focuses on epidemiological<br />
studies of cancer examining differential<br />
cancer risks among U.S. Hispanics for both<br />
adults and children. The results of this research<br />
are intended to better inform cancer control and<br />
prevention efforts in Florida among various subpopulations.<br />
Currently, Dr. Wilkinson is part of a<br />
collaborative team, led by investigators from the<br />
International Agency for Research on <strong>Cancer</strong>, to<br />
study prostate cancer genetics in Cuban men,<br />
comparing populations from Havana and Miami.<br />
An application for project funding to the NCI is<br />
planned for <strong>2004</strong>.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Wilkinson, JD, Wohler-Torres, B, Trapido, E,<br />
Fleming, LE, MacKinnon, J, Voti, L, and Peace,<br />
S. <strong>Cancer</strong> trends among Hispanic men in South<br />
Florida, 1981-1998. <strong>Cancer</strong> 94:1183-90, 2002.<br />
Wilkinson, JD, Wohler-Torres, B, Trapido, E,<br />
Fleming, LE, MacKinnon, J, and Peace, S. <strong>Cancer</strong><br />
among Hispanic women in South Florida: an<br />
18-year assessment: a report from the Florida<br />
<strong>Cancer</strong> Data System. <strong>Cancer</strong> 95:1752-58, 2002.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Florida’s Hispanic children have a 30 percent<br />
increased risk of lymphoma and lymphoid leukemia<br />
compared to non-Hispanic White children.<br />
• <strong>Cancer</strong> incidence is decreased for both Hispanic<br />
men and women in South Florida compared to<br />
non-Hispanic Whites.<br />
• Lung cancer is now the third most common<br />
cancer among Hispanic women in South<br />
Florida.<br />
• Similarly, cancer mortality is decreasing among<br />
the Hispanic and non-Hispanic populations of<br />
South Florida.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 31
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32<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
C L I N I C A L O N C O L O G Y R E S E A R C H<br />
P R O G R A M<br />
PROGRAM LEADER<br />
Joseph D. Rosenblatt, M.D.<br />
Professor of Medicine and Division Chief of Hematology-Oncology<br />
PROGRAM CO-LEADER<br />
Kelvin P. Lee, M.D.<br />
Associate Professor of Microbiology and Immunology<br />
PROGRAM DESCRIPTION<br />
The Clinical Oncology Research Program<br />
(CORP) is composed of 23 faculty members<br />
as well as associate faculty members from accross<br />
the University of Miami School of Medicine. Faculty<br />
are specifically selected for their involvement<br />
in research that has significant translational potential<br />
and may lead to improvements in cancer<br />
prevention, diagnosis, and treatment. Program<br />
members must have peer-reviewed cancer-related<br />
research funding or be newly recruited investigators<br />
with the potential to apply for and receive<br />
funding. Associate program members generally<br />
are clinical faculty who are selected based on<br />
significant involvement in the overall clinical<br />
research effort at the University, such as involvement<br />
in clinical trials and/or correlative studies.<br />
The program was organized in January 2003<br />
to address the need for a broad-based clinical<br />
research program distinct from the four multidisciplinary<br />
research programs at the University<br />
of Miami <strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong>.<br />
Nearly half of the program members are<br />
newly recruited faculty.<br />
GOALS OF PROGRAM<br />
The overall goal of the CORP is to translate<br />
findings from UM/<strong>Sylvester</strong>’s basic research<br />
programs into new therapeutic, diagnostic, and/<br />
or prognostic interventions, as well as develop<br />
novel and innovative clinical trials.<br />
Specific goals include:<br />
1) Translating UM/<strong>Sylvester</strong>’s basic science efforts<br />
into the clinical arena. This includes the preclinical<br />
and clinical development of novel diagnostic<br />
and therapeutic strategies and their<br />
implementation in the form of clinical protocols<br />
by CORP investigators.<br />
2) Integrating clinical research efforts across<br />
departmental lines. This includes support for<br />
site-based disease approaches encompassing<br />
tissue procurement for analysis and validation,<br />
improved mechanisms for tissue preservation<br />
to facilitate analysis of gene expression,<br />
proteomics, and coordination of efforts<br />
involving basic scientists, surgical staff,<br />
and pathologists.<br />
3) Developing the institutional intramural trial<br />
portfolio in an effort to provide novel clinical<br />
options for UM/<strong>Sylvester</strong> patients and to<br />
develop pilot phase I/II trials for subsequent<br />
validation in the cooperative group setting.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 33
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
Several shared interests connect researchers<br />
and create natural liaisons with other UM/<strong>Sylvester</strong><br />
programs. Areas of interest include:<br />
• Development of gene and cellular therapies for<br />
cancer.<br />
• Development of novel pharmacological agents<br />
and/or combinations.<br />
• Identification of new prognostic and/or therapeutic<br />
targets.<br />
• Creation of mechanisms for tissue procurement<br />
and/or correlative studies.<br />
CORP members are involved in the development<br />
and management of several shared resources<br />
including Clinical Research Services; tumor banks<br />
and databases for breast cancer, and more recently,<br />
lymphoma; and a Cell Banking and Purification<br />
Facility for the study of hematological malignancies.<br />
The CORP also serves as the major access<br />
point to the University of Miami’s general clinical<br />
research center for clinical oncology research.<br />
The CORP meets on a monthly basis and<br />
invites investigators from other multidisciplinary<br />
research programs to share findings in a group<br />
forum designed to foster translation and application<br />
to the clinical arena. Recent CORP initiatives<br />
include the testing of a locally developed<br />
antibody to CD30 for treatment of Hodgkin’s<br />
and non-Hodgkin’s lymphomas, testing of novel<br />
genetically engineered lung cancer vaccines in<br />
phase I/II trials, novel radio-sensitizers, identification<br />
of new molecular prognostic factors in lymphoma<br />
and breast cancer, and the targeting of<br />
non-dividing anaerobic tumor cells using glycolytic<br />
inhibitors. The CORP continues to promote<br />
the identification and adaptation of promising<br />
strategies developed by UM/<strong>Sylvester</strong> basic scientists<br />
for clinical application.<br />
PARTICIPANTS<br />
Benedetto, Pasquale W., M.D.<br />
Medicine<br />
Feun, Lynn G., M.D.<br />
Medicine<br />
Ganju-Krishan, Awtar, Ph.D.<br />
Radiation Oncology<br />
Greer, Sheldon, Ph.D.<br />
Microbiology and Immunology<br />
Koniaris, Leonidas G., M.D., F.A.C.S.<br />
Surgery<br />
Lampidis, Theodore J., Ph.D.<br />
Cell Biology and Anatomy<br />
Lee, Kelvin P., M.D.<br />
Microbiology and Immunology<br />
Lipshultz, Steven E., M.D.<br />
Pediatrics<br />
Lokeshwar, Balakrishna L., Ph.D.<br />
Urology<br />
Lokeshwar, Vinata B., Ph.D.<br />
Urology<br />
Lossos, Izidore, M.D.<br />
Medicine<br />
Milikowski, Clara, M.D.<br />
Pathology<br />
Raez, Luis E., M.D., F.A.C.P.<br />
Medicine<br />
Rocha Lima, Caio Max S., M.D.<br />
Medicine<br />
Rosenblatt, Joseph D., M.D.<br />
Medicine<br />
Savaraj, Niramol, M.D.<br />
Medicine<br />
Singal, Rakesh, M.D.<br />
Medicine<br />
Slingerland, Joyce M., M.D., Ph.D., F.P.R.C.(C)<br />
Medicine<br />
Soloway, Mark S., M.D.<br />
Urology<br />
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UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
Tang, Shou-Ching, M.D., Ph.D.<br />
Medicine<br />
Tolba, Khaled A., M.D.<br />
Medicine<br />
Vincek, Vladimir, M.D., Ph.D.<br />
Pathology<br />
Wolfson, Aaron H., M.D.<br />
Radiation Oncology<br />
LYNN G. FEUN, M.D.<br />
Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Feun’s research focuses on developing<br />
novel treatment strategies for patients with<br />
melanoma, liver cancer, and brain tumors.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Feun, L, Modiano, M, Lee, K, Mao, J, Marini, A,<br />
Savaraj, N, Plezia, P, Almassian, B, Colacino, E,<br />
Fischer, J, and MacDonald, S. Phase I and pharmacokinetic<br />
study of 3-aminopyridine-2-<br />
carboxaldehyde thiosemicarbazone (3-AP) using a<br />
single intravenous dose schedule. <strong>Cancer</strong> Chemotherapy<br />
and Pharmacology 50:223-29, 2002.<br />
Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG,<br />
Xu, R, Xu, J, and Savaraj, N. Procollagen-like<br />
protein as a molecular target in the treatment of<br />
primary brain tumor. ScientificWorldJournal<br />
2:125-26, 2002.<br />
Feun, LG, Savaraj, N, Hurley, J, and Marini, A.<br />
Phase II trial of Paclitaxel and Dacarbazine with<br />
filgrastim administration in advanced malignant<br />
melanoma. <strong>Cancer</strong> Investigation 20:357-61,<br />
2002<br />
study comparing combined treatment with histamine<br />
dihydrochloride plus interleukin-2 versus<br />
interleukin-2 alone in patients with metastatic<br />
melanoma. Journal of Clinical Oncology 20:125-<br />
33, 2002<br />
2003<br />
Feun, LG, O’Brien, C, Molina, E, Rodriguez, M,<br />
Jeffers, L, Schiff, ER, Marini, A, Savarj, N, and<br />
Ardalan, B. Recombinant leukocyte interferon,<br />
doxorubicin, and 5FUDR in patients with hepatocellular<br />
carcinoma-a phase II trial. Journal of<br />
<strong>Cancer</strong> Research and Clinical Oncology 129:17-<br />
20, 2003<br />
Prados, MD, Schold, SC JR SC, Fine, HA,<br />
Jaeckle, K, Hochberg, F, Mechtler, L, Fetell, MR,<br />
Phuphanich, S, Feun, L, Janus, TJ, Ford, K, and<br />
Graney, W. A randomized, double-blind, placebo-controlled,<br />
phase II study of RMP-7 in<br />
combination with carboplatin administered intravenously<br />
for the treatment of recurrent malignant<br />
glioma. Journal of Neuro-Oncology 5:96-110,<br />
2003<br />
Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L,<br />
Donnelly, E, Solomon, J, Sundaram, M, Feun,<br />
LG, and Savaraj, N. Phase II study of vinorelbine<br />
with low dose prednisone in the treatment of<br />
hormone-refractory metastatic prostate cancer.<br />
Oncology Reports 10:885-89, 2003<br />
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,<br />
Lampidis, T, Robles, C, Furst, AJ, and Feun, LG.<br />
Overexpression of mutated MRP4 in cisplatin<br />
resistant small cell lung cancer cell line: collateral<br />
sensitivity to azidothymidine. International Journal<br />
of Oncology 23:173-79, 2003<br />
Agarwala, SS, Glaspy, J, O’Day, SJ, Mitchell, M,<br />
Gutheil, J, Whitman, E, Gonzalez, R, Hersh, E,<br />
Feun, LG, Belt, R, Meyskens, F, Hellstrand, K,<br />
Wood, D, Kirkwood, JM, Gehlsen, KR, and<br />
Naredi, P. Results from a randomized phase III<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 35
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
HIGHLIGHTS/DISCOVERIES<br />
• Collaborated on a phase I trial of arginine<br />
deiminase in melanoma with promising results.<br />
A phase II protocol currently is under development.<br />
• Developed a phase I clinical trial for patients<br />
whose brain tumors expressed a procollagenlike<br />
protein, based on Dr. Feun and Niramol<br />
Savaraj, M.D.’s in vitro discovery that this<br />
protein may predict clinical response to vitamin<br />
D therapy. This trial has been approved by the<br />
Institutional Review Board (IRB); the Investigational<br />
New Drug (IND) application is under<br />
review by the Food and Drug Administration<br />
(FDA).<br />
AWTAR GANJU-KRISHAN, PH.D.<br />
Professor of Radiation Oncology<br />
DESCRIPTION OF RESEARCH<br />
Most of Dr. Krishan’s current research<br />
focuses on:<br />
• Monitoring of nuclear hormone receptor expression<br />
in human breast and prostate tumors.<br />
Dr. Krishan has developed flow cytometric<br />
methods for determining estrogen, androgen,<br />
and vitamin D receptor expression in archival<br />
human tumors. These methods recently have<br />
been used to determine expression in human<br />
male and female breast tumors and prostate<br />
tumors.<br />
• Evaluating a novel apoptosis assay with antibodies<br />
to ssDNA using flow cytometry; Dr.<br />
Krishan and Oscar Frankfurt, Ph.D., (University<br />
of Miami) have been studying the use of a<br />
novel method for discriminating between<br />
apoptotic and the necrotic cells by laser flow<br />
cytometry, which was recently published.<br />
• Evaluating tumor cells in body fluids using high<br />
resolution flow cytometry; Dr. Krishan and his<br />
colleagues have recently developed a high resolution<br />
flow cytometer with funding from NASA<br />
and the American <strong>Cancer</strong> Society (ACS). This<br />
instrument can measure nuclear volume and<br />
thus discriminate between normal and tumor<br />
cells. Supported by an exploratory grant from<br />
the NIH-NCI, they are currently examining the<br />
potential of this technique for detecting occult<br />
tumor cells in body fluids from cancer patients.<br />
• Studying androgen receptor expression in human<br />
prostate tumors; Dr. Krishan and May<br />
Abdel-Wahab, M.D., Ph.D., have used flow<br />
cytometric methods to correlate receptor expression<br />
with clinical response in patients on<br />
the Radiation Therapy Oncology Group’s<br />
(RTOG) study of radiation and hormone<br />
therapy in prostate cancer patients.<br />
• Evaluating DNA aneuploidy and S-phase fraction<br />
as indicators of response to chemoradiotherapy<br />
in patients with invasive cervical<br />
carcinoma; Dr. Krishan, Aaron H. Wolfson,<br />
M.D., and Daniel Estape, M.D., are involved<br />
in this project, which is funded by the RTOG<br />
and seeks to use high-resolution flow cytometry<br />
for the analysis of aneuploidy and cell cycle distribution<br />
in human cervical cancer under a<br />
University of Miami IRB-approved protocol.<br />
• Organizing annual Indo-U.S. workshops in<br />
cytomics. These workshops include six to ten<br />
U.S. faculty members along with their Indian<br />
counterparts, who teach the latest methods in<br />
flow cytometry in India. Up to 50 researchers<br />
attend these workshops, and so far, four workshops<br />
have been held in research institutes/<br />
universities in Chandigarh, Hyderabad, Jammu,<br />
and Bombay.<br />
36<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
SELECTED PUBLICATIONS<br />
2002<br />
Krishan, A. Flow cytometric monitoring of hormone<br />
receptor expression in human solid tumors.<br />
Proceedings of SPIE 4622: 211-17, 2002.<br />
Arya, P, Andritsch, IH, and Krishan, A. Androgen<br />
receptor expression in archival human breast<br />
tumors. Methods in Cell Science 24:61-64, 2002.<br />
Krishan, A. Flow cytometric monitoring of drug<br />
resistance in human tumor cells. Methods in Cell<br />
Science 24:55-60, 2002.<br />
Thomas, RA, Krishan, A, and Brochu, M. High<br />
resolution flow cytometric analysis of electronic<br />
nuclear volume and DNA content in normal and<br />
abnormal human tissue. Methods in Cell Science<br />
24:11-18, 2002.<br />
Adiga, SK, Andritsch, IH, Rao, RV, and Krishan,<br />
A. Androgen receptor expression and DNA content<br />
of paraffin-embedded archival human prostate<br />
tumors. Cytometry 50:25-30, 2002.<br />
2003<br />
Frankfurt, OS and Krishan, A. Apoptosis-based<br />
drug screening and detection of selective toxicity<br />
to cancer cells. Anticancer Drugs 14:555-61,<br />
2003.<br />
Frankfurt, OS and Krishan, A. Microplate<br />
screening for apoptosis with antibody to singlestranded<br />
DNA distinguishes anticancer drugs<br />
from toxic chemicals. Journal of Biomolecular<br />
Screening 8:185-90, 2003.<br />
Frankfurt, OS and Krishan, A. Apoptosis enzyme-linked<br />
immunosorbent assay distinguishes<br />
anticancer drugs from toxic chemicals and predicts<br />
drug synergism. Chemico-biological Interactions<br />
145:89-99, 2003.<br />
Krishan, A. Flow cytometric monitoring of drug<br />
resistance in human tumor cells. Methods in Cell<br />
Science 24:55-60, 2003.<br />
Abdel-Wahab, M, Krishan, A, Milikowski, C,<br />
Wahab, AA, Walker, G, and Markoe, A. Androgen<br />
receptor antigen density and S-phase fraction<br />
in prostate cancer: a pilot study. Prostate <strong>Cancer</strong><br />
and Prostatic Disease 6:294-300, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Developed Krishan’s propidium iodide/hypotonic<br />
citrate method for rapid determination of<br />
cellular DNA content and cell cycle traverse.<br />
This method is universally used for rapid cell<br />
cycle analysis by flow cytometry.<br />
• Developed flow cytometric assays for drug<br />
transport and efflux. This rapid method is now<br />
universally used as a functional assay for drug<br />
resistance.<br />
• Developed flow cytometric methods for rapid<br />
determination of nuclear hormone receptor expression<br />
in human archival tumors.<br />
• Developed the NASA/ACS flow cytometer,<br />
which now is sold by NPE Systems Inc., as a<br />
commercial unit for rapid determination of<br />
cellular volume and DNA content.<br />
SHELDON GREER, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Greer’s laboratory has developed a drug<br />
that selectively radiosensitizes human tumors.<br />
The drug is 5-chloro-2'-deoxycytidine<br />
(cytochlor). When it is coadministered with<br />
tetrahydrouridine (H 4<br />
U), an inhibitor of its preliminary<br />
systemic deamination before it reaches<br />
the tumor site, it has been shown to be efficacious<br />
versus seven rodent tumors and seven human<br />
tumors in nude mice. For example, with a<br />
rodent mammary adenocarcinoma, 80 percent<br />
cures were obtained with weight loss no greater<br />
than that obtained with radiation alone. This was<br />
confirmed by an independent blind study. Similar<br />
response was obtained with human tumors,<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 37
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
which included two prostatic tumors, three head<br />
and neck tumors, a glioblastoma, a lung tumor,<br />
and a breast tumor.<br />
Cytochlor has resulted in a three-fold dose<br />
increase effect, meaning that a dose of 70 Gy is<br />
equivalent to a dose of 210 Gy to the tumor<br />
without damage to underlying tissue. The success<br />
of the radiosensitizer can be understood in view<br />
of several biochemical studies that show: 1) 99<br />
percent of the cells of a human prostate tumor<br />
and a head and neck tumor incorporated the<br />
radiosensitizer into DNA, 2) 40 percent of thymine<br />
was replaced by 5-chlorouracil in DNA of<br />
tumor cells, 3) all tumors obtained from patients<br />
with head and neck tumors had elevated levels<br />
over that of normal tissue of one of the two enzymes,<br />
which anabolize cytochlor to become a<br />
radiosensitizer, and 50 percent of patients had<br />
elevations of both enzymes (averaging greater<br />
than 10-fold), 4) 5-chlorouracil derived from<br />
cytochlor is not removed from DNA as is 5-<br />
iodoruacil (the first generation radiosensitizer), 5)<br />
5-CldUMP derived from cytochlor inhibits<br />
thymidylate synthetase as effectively as<br />
FdUMP—this prevents the formation of TTP,<br />
the competitor to the incorporation of CldUTP,<br />
and 6) CldUTP activates dendritic cell (DC)<br />
kinase, the enzyme responsible for the first step<br />
in the anabolism of cytochlor.<br />
Studies commissioned by the NCI have<br />
shown that cytochlor did not display any clinical<br />
signs of toxicity to primates when given the drug<br />
five days per week for three weeks. No toxicity<br />
was seen in mice and dogs where it was shown<br />
that H 4<br />
U extended the half life and increased the<br />
selectivity of cytochlor. The drug is awaiting IND<br />
approval by the FDA and will be tested in a phase<br />
I clinical trial at UM/<strong>Sylvester</strong> in patients with<br />
squamous cell carcinoma (SCCA) of the oropharynx<br />
and oral cavity.<br />
Dr. Greer also has discovered an approach to<br />
tumors that arise or are successful as a result of<br />
gene silencing. These include tumors due to the<br />
silencing of genes, encoding tumor suppressor<br />
genes, repair enzymes, migration suppressor glycoproteins<br />
such as cadherin, estrogen receptors,<br />
enzymes protecting cells, oxidative damage, antiangiogenesis<br />
factors, and factors that prevent the<br />
tumors from being controlled by the patient’s<br />
immune system. The drug, called zebularine, can<br />
be administered orally and is non-toxic. The NCI<br />
has ordered the development of this drug after<br />
studies in nude mice showed its effectiveness.<br />
The drug also has the potential to be utilized in<br />
patients with abnormal globin gene expression<br />
(hemoglobinopathies) and abnormalities in the<br />
immune system.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Cheng, JC, Matsen, CB, Gonzales, FA, Ye, W,<br />
Greer, S, Marquez, VE, Jones, PA, and Selker,<br />
EU. Inhibition of DNA methylation and reactivation<br />
of silenced genes by zebularine. Journal of<br />
the National <strong>Cancer</strong> Institute March 5; 95:399-<br />
409, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Developed and tested cytochlor, in collaboration<br />
with the NCI, which is now under review<br />
by the FDA for clinical application and testing.<br />
• Developed zebularine in cooperative studies<br />
including the University of Oregon, the University<br />
of Southern California, the NIH, and the<br />
University of Miami. Zebularine is approved for<br />
further development by the NIH.<br />
• Developed an approach for chemotherapy or<br />
radiation therapy based on the enzymatic profile<br />
of human tumors and adjacent normal tissue<br />
with respect to four enzymes involved in<br />
nucleic acid metabolism. The study requires a<br />
small amount of biopsy material. The approach<br />
is novel in that it involves several (nine) antimetabolites<br />
including cytochlor and zebularine,<br />
which have never been used in humans. The<br />
novel approach also involves gene therapy combined<br />
with radiation therapy, allowing greater<br />
selectivity than gene therapy combined with<br />
chemotherapy because of the very nature of<br />
external beam radiation therapy.<br />
38<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
LEONIDAS G. KONIARIS, M.D., F.A.C.S.<br />
Associate Professor of Surgery<br />
DESCRIPTION OF RESEARCH<br />
Dr. Koniaris’ research concentrates on the<br />
mechanism of growth control and deregulation<br />
in vivo in the gastrointestinal (GI) tract and<br />
breast. In particular, he has focused on the role of<br />
two secreted factors—interleukin-6 (IL-6) and<br />
macrophage inflammatory cytokine-1 (MIC-1).<br />
IL-6 is a pro-inflammatory cytokine essential<br />
in normal liver homeostasis. Investigators in the<br />
laboratory have recently demonstrated that IL<br />
functions as a growth factor for hepatocytes<br />
through an apparent direct mechanism that does<br />
not involve activation of cMET or epidermal<br />
growth factor (EGF). Subsequent work has demonstrated<br />
that this mitogenic response is associated<br />
with profound anti-apoptotic activity. Other<br />
work from the laboratory has examined how the<br />
IL-6 response affects insulin signaling and contributes<br />
to the hepatocellular dysfunction seen in<br />
chronic liver disease. In addition, they are examining<br />
the effects of IL-6 on hepatocellular carcinoma<br />
with collaborators at the University of<br />
North Carolina.<br />
MIC-1 is a divergent member of the transforming<br />
growth factor-beta (TGF-β) superfamily<br />
of growth and differentiation factors. MIC-1<br />
strongly has been implicated in the pathogenesis<br />
of both colorectal and prostate cancers and may<br />
have a potent anti-tumor function. The laboratory<br />
has examined the expression of MIC-1 and<br />
found it to be an immediate early response to a<br />
variety of organ injuries and exposures to carcinogens.<br />
They have generated MIC-1 null mice and<br />
are examining their propensity to the development<br />
of liver, colorectal, breast, and prostate<br />
cancers.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Barreiro, CJ, Lillemoe, KD, Koniaris, LG, Sohn,<br />
TA, Yeo, CJ, Coleman, J, Fishman, EK, and<br />
Cameron, JL. Diagnostic laparoscopy for<br />
periampullary and pancreatic cancer: what is the<br />
true benefit? Journal of Gastrointestinal Surgery<br />
6:75-81, 2002.<br />
Kovach, SJ, Hendrickson, RJ, Cappadona, CR,<br />
Schmidt, CM, Groen, K, Koniaris, LG, and<br />
Sitzmann, JV. Cryoablation of unresectable pancreatic<br />
cancer. Surgery 131:463-64, 2002.<br />
Sayeed, S, Koniaris, LG , and Papadakos, PJ. Image<br />
of the month. Acute respiratory distress syndrome.<br />
Archives of Surgery 137:491-92, 2002.<br />
Abt, PL, Halaby, I, Schoeniger, LO, and<br />
Koniaris, LG. Intrahepatic gas. Journal of the<br />
American College of Surgeons 195:129, 2002.<br />
Cirillo, RL Jr. and Koniaris, LG. Detecting blunt<br />
pancreatic injuries. Journal of Gastrointestinal<br />
Surgery 6:587-98, 2002.<br />
Hendrickson, RJ, Koniaris, LG, Kovach, SJ, and<br />
Johnson, JA. Gamma probe-confirmed<br />
laparoscopic accessory splenectomy. Surgical Endoscopy<br />
16:1364, 2002.<br />
Hendrickson, RJ, Koniaris, LG, Schoeniger, LO,<br />
Strang, J, Killackey, MA, and Peacock, JL. Small<br />
bowel obstruction due to a paracolonic retroperitoneal<br />
hernia. American Journal of Surgery<br />
68:756-58, 2002.<br />
Sayeed, S, Koniaris, LG , Kovach, SJ, and<br />
Hirokawa, T. Torsion of a wandering spleen. Surgery<br />
132:535-36, 2002.<br />
Ognibene. SJ, Koniaris. LG, Pegoli, W Jr., and<br />
Drugas, GT. Intraoperative colonic lavage in a<br />
premature infant: a case report. Journal of Pediatric<br />
Surgery 37:1645-47, 2002.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 39
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
Price, JA, Kovach, SJ, Johnson, T, Koniaris, LG ,<br />
Cahill, PA, Sitzmann, JV, and McKillop, IH. Insulin-like<br />
growth factor I is a comitogen for hepatocyte<br />
growth factor in a rat model of<br />
hepatocellular carcinoma. Hepatology 36:1089-<br />
97, 2002.<br />
Hendrickson, RJ, Koniaris, LG, Jiang, S,<br />
Waldman, D, Massey, HT, and Sitzmann, JV.<br />
Purposeful delay in the repair of a traumatic left<br />
common carotid pseudoaneurysm in a bovine<br />
aortic arch presenting as a widened mediastinum.<br />
Journal of Trauma 53:1166-69, 2002.<br />
Sitzmann, JV and Koniaris, LG. Intra-arterial<br />
hepatic catheterization and pump placement.<br />
Operative Techniques in General Surgery 4:99-<br />
110, 2002<br />
Zimmers, TA, Davies, MV, Koniaris, LG,<br />
Haynes, P, Tomkinson, KN, McPherron, AC,<br />
Wolfman, NM, and Lee SJ. Cachexia induced<br />
by systemic myostatin administration in mice.<br />
Science 296:1486-88, 2002.<br />
2003<br />
Koniaris, LG. Induction of MIC-1/growth differentiation<br />
factor-15 following bile duct injury.<br />
Journal of Gastrointestinal Surgery 7:901-5,<br />
2003.<br />
Koniaris, LG, Seibel, JA, Geschwind, JF, and<br />
Sitzmann, JV. Can ethanol therapies injure the<br />
bile ducts? Hepato-gastroenterology 50:69-72,<br />
2003.<br />
Hendrickson, RJ, Diaz, AA, Salloum, R, and<br />
Koniaris, LG. Benign rectal ulcer: an underground<br />
cause of inpatient lower gastrointestinal<br />
bleeding. Surgical Endoscopy17:1759-65, 2003.<br />
Koniaris, LG, Schoeniger, LO, Kovach, S, and<br />
Sitzmann, JV. The quick, no-twist, no-kink portal<br />
confluence reconstruction. Journal of the<br />
American College of Surgeons 196:490-94, 2003.<br />
Schoeniger, LO, Bankey, P, Drugas, GT, and<br />
Koniaris, LG. Optimal closure of the complex<br />
abdomen. Archives of Surgery 138:458, 2003.<br />
Koniaris. LG, Drugas. G, Katzman. PJ, and<br />
Salloum, R. Management of gastrointestinal lymphoma.<br />
Journal of the American College of Surgeons<br />
197:127-41, 2003.<br />
Koniaris, LG, Wilson, S, Drugas, G, and<br />
Simmons, W. Capnographic monitoring of ventilatory<br />
status during moderate (conscious) sedation.<br />
Surgical Endoscopy 17:1340, 2003.<br />
Koniaris, LG, McKillop, IH, Schwartz, SI, and<br />
Zimmers, TA. Liver regeneration. Journal of the<br />
American College of Surgeons 197:634-59, 2003.<br />
Zimmers, TA, McKillop, IH, Pierce, RH, Yoo,<br />
JY, and Koniaris, LG. Massive liver growth in<br />
mice induced by systemic interleukin 6 administration.<br />
Hepatology 38:326-34, 2003.<br />
Senn, JJ, Klover, PJ, Nowak, IA, Zimmers, TA,<br />
Koniaris, LG, Furlanetto, RW, and Mooney, RA.<br />
Suppressor of cytokine signaling-3 (SOCS-3), a<br />
potential mediator of interleukin-6-dependent<br />
insulin resistance in hepatocytes. Journal of Biological<br />
Chemistry 278:13740-46, 2003.<br />
Klover, PJ, Zimmers, TA, Koniaris, LG, and<br />
Mooney, RA. Chronic exposure to interleukin-6<br />
causes hepatic insulin resistance in mice. Diabetes<br />
52:2784-89, 2003.<br />
THEODORE J. LAMPIDIS, PH.D.<br />
Professor of Cell Biology and Anatomy<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lampidis’ research has evolved from his<br />
preliminary work on the physiology and<br />
pharmacology of cultured cardiac cells. A video/<br />
electronic-computerized system was developed to<br />
monitor cardiac cell function in vitro. Using pulsating<br />
myocardial cells as a model, he focused on<br />
why the widely used anti-tumor agent, Adriamycin,<br />
affected the hearts of patients treated with this<br />
drug. This initial idea led Dr. Lampidis to study<br />
drug selectivity between certain types of tumor<br />
and normal cells and the chemical requirements<br />
40<br />
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of anti-cancer drugs for reduced cardiotoxicity<br />
and increased tumoricidal potency.<br />
Dr. Lampidis’ efforts then turned toward<br />
understanding the mechanisms of drug resistance<br />
to mitochondrial agents such as rhodamine 123<br />
and the structure/function requirements of various<br />
chemotherapeutic agents for recognition by<br />
p-glycoprotein (Pgp)-mediated multiple drug<br />
resistance (MDR). Molecular and immunochemical<br />
probes of MDR and other cellular<br />
resistance mechanisms (i.e., multi-drug resistance-related<br />
protein), were developed to detect<br />
and study these phenomena. He and his colleagues<br />
found that chemical charge and lipophilicity<br />
play critical roles in determining<br />
whether anticancer drugs are recognized by tumor<br />
cells expressing these MDR mechanisms.<br />
As an outcome of their studies on mitochondrial<br />
agents, these researchers realized that tumor<br />
cells treated with the uncoupling agent, rhodamine<br />
123, were strikingly similar to the poorly oxygenated<br />
cancer cells located at the inner core of solid<br />
tumors. In both conditions, the cells rely exclusively<br />
on anaerobic metabolism for survival.<br />
Moreover, cells in the center of a tumor divide<br />
more slowly than outer-growing aerobic cells and<br />
consequently are more resistant to standard chemotherapeutic<br />
agents, which target the more<br />
rapidly dividing cells. Thus, by the nature of their<br />
slow growth, these tumor cells exhibit a form of<br />
MDR, which contributes significantly to chemotherapy<br />
failures in the treatment of solid tumors.<br />
Anaerobiosis, however, also provides a natural<br />
window of selectivity for agents that interfere<br />
with glycolysis. This concept forms the basis for<br />
Dr. Lampidis’ current initiative of exploiting the<br />
natural selectivity that inhibitors of glycolysis<br />
should have for hypoxic cells that are slowly<br />
growing at the inner core of solid tumors. His<br />
background and work on mitochondrial localizing<br />
drugs and MDR uniquely position him to<br />
stimulate new initiatives in this promising area of<br />
research.<br />
A long-term goal for Dr. Lampidis is the addition<br />
of the appropriate glycolytic inhibitors<br />
(which are presently being designed and synthesized)<br />
to current clinical protocols, which may<br />
significantly improve the success rate of cancer<br />
chemotherapy. Moreover, studying how tumor<br />
cells react to combinations of oxidative phosphorylation<br />
and glycolytic inhibitors could lead to<br />
the design of future novel approaches to more<br />
successfully treat cancer.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ .<br />
Hypoxia increases tumor cell sensitivity to glycolytic<br />
inhibitors: a strategy for solid tumor therapy<br />
(Model C). Biochemical Pharmacology 64:1745-<br />
51, 2002.<br />
2003<br />
Savaraj N, Wu, C, Wangpaichitr, M, Kuo, MT,<br />
Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L.<br />
Overexpression of mutated MRP4 in cisplatin<br />
resistant small cell lung cancer cell line: collateral<br />
sensitivity to azidothymidine. International Journal<br />
of Oncology 23:173-79, 2003.<br />
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and<br />
Lampidis, TJ . Multidrug resistance correlates<br />
with overexpression of Muc4 but inversely with<br />
P-glycoprotein and multidrug resistance related<br />
protein in transfected human melanoma cells.<br />
Biochemical Pharmacology 65:1419-25, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• In osteosarcoma, wild type (wt) cells treated<br />
with agents that inhibit mitochondrial oxidative<br />
phosphorylation (OXPHOS) by interacting<br />
with complexes I, III, and V of the electron<br />
transport chain in different ways—rhodamine<br />
123 (Rho-123), rotenone, oligomycin, and antimycin<br />
A—all of the agents were found to hypersensitize<br />
wt cells to the glycolytic inhibitors<br />
2-deoxyglucose (2-DG) and oxamate.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 41
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
• In ρ 0 cells that have lost their mitochondrial<br />
DNA and therefore cannot undergo OXPHOS,<br />
cells were found to be ten and 4.9 times more<br />
sensitive to 2-DG and oxamate, respectively,<br />
than wt cells.<br />
• Lactic acid levels, which are a measure of<br />
anaerobic metabolism, were found to be greater<br />
than three times higher in ρ 0 than in wt cells.<br />
Moreover, when wt cells were treated with rho<br />
123, lactic acid amounts increased as a function<br />
of increasing rho 123 doses. Under similar rho<br />
123 treatment, ρ 0 cells did not increase their<br />
lactic acid levels. These data confirm these different<br />
cell models are similarly sensitive to glycolytic<br />
inhibitors due to their dependence on<br />
anaerobic metabolism.<br />
• These results suggest that inner core tumor cells<br />
are more dependent on glycolysis than outer<br />
growing aerobic cells, which provides a window<br />
of selectivity that can be exploited therapeutically.<br />
Thus, glycolytic inhibitors could be used<br />
to specifically target the hypoxic slow-growing<br />
cells of solid tumors and thereby increase the<br />
efficacy of current chemotherapeutic and irradiation<br />
protocols designed to kill rapidly-dividing<br />
cells. Moreover, glycolytic inhibitors could<br />
be particularly useful in combination with antiangiogenic<br />
and anti-hypoxic inducible factor<br />
(HIF) agents, which a priori, should make tumors<br />
more anaerobic.<br />
• Recently, Dr. Lampidis has provided proof of<br />
principle in two animal models of human cancer<br />
(non-small cell lung and osteosarcoma) that<br />
the addition of the glycolytic inhibitor 2-DG<br />
(which targets the slowly growing hypoxic cells<br />
of a tumor), increases the efficacy of standard<br />
chemotherapeutic agents (which target the rapidly<br />
growing aerobic cells) in reducing tumor<br />
size and prolonging survival. In collaboration<br />
with Threshold Pharmaceuticals, the NCI, and<br />
UM/<strong>Sylvester</strong>, they have received FDA approval<br />
and are now nearing the first human trials testing<br />
his strategy.<br />
KELVIN P. LEE, M.D.<br />
Associate Professor of Microbiology<br />
and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Research in Dr. Lee’s laboratory focuses on<br />
the cells and molecules that play central roles<br />
in initiating the adaptive immune response.<br />
Understanding these interactions is essential for<br />
developing effective immune-based therapies<br />
against cancer. At the cellular level, they are<br />
specifically studying the dendritic cells (DC),<br />
which are thought to be the most important professional<br />
antigen presenting cell (APC). Because<br />
DC monitor the local environment for immunologic<br />
“danger” signals and control what antigens<br />
are presented to T cells to activate them, they are<br />
positioned to regulate the initiation of immune<br />
responses. Their work has examined how DC<br />
arise from hematopoietic progenitors and their<br />
intracellular/genetic characteristics. Dr. Lee and<br />
his colleagues have previously reported that activation<br />
of the protein kinase C (PKC) intracellular<br />
signal transduction pathway in human hematopoietic<br />
CD34 + stem cells causes direct differentiation<br />
to a pure population of DC. Thus, PKC<br />
signaling specifically triggers the DC differentiation<br />
“program” in these cells. Additionally, specific<br />
isoforms of PKC appear to regulate specific<br />
aspects of DC differentiation. Ongoing studies<br />
are seeking to completely characterize the components<br />
of the PKC signaling pathway and what<br />
genetic events are triggered by this signal.<br />
From a translational standpoint, researchers<br />
in Dr. Lee’s laboratory have found that in addition<br />
to normal cells, PKC activation can drive<br />
DC differentiation in acute and chronic myeloid<br />
leukemic blasts. Because these “leukemic” DC<br />
retain the ability to activate T cells and are endogenously<br />
loaded with leukemia antigens, they<br />
potentially can be used as “cellular” anti-leukemia<br />
vaccines by re-infusion back into patients. This<br />
work aims to bring this approach to clinical trials.<br />
In addition to the DC studies, a clinical trial<br />
(headed by Dr. Lee) and basic laboratory research<br />
42<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
currently are looking at novel agents against<br />
multiple myeloma (MM). The NCI-sponsored<br />
phase I/II clinical trial is examining arsenic trioxide<br />
+ ascorbic acid in the treatment of refractory/<br />
relapsed MM. Initial results demonstrate that this<br />
combination is effective against myeloma that is<br />
resistant to standard chemotherapy (including<br />
thalidomide) with acceptable toxicity. The laboratory<br />
component of these studies seeks to understand<br />
how arsenic kills myeloma, how ascorbic<br />
acid potentiates that killing, how myeloma cells<br />
become resistant to arsenic, and which host<br />
(i.e., patient) factors may help the myeloma<br />
survive in the bone marrow.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Gray Parkin, K, Stephan, RP, Apilado, RG, Lill-<br />
Elghanian, DA, Lee, KP, Saha, B, and Witte, PL.<br />
Expression of CD28 by bone marrow stromal<br />
cells and its involvement in B lymphopoiesis.<br />
Journal of Immunology 169:2292-302, 2002.<br />
Baumgartner, R, Durant, P, van Gessel, Y,<br />
Chattopadhyay, S, Beswick, RL, Tadaki, DK,<br />
Lasbury, M, Lee, CH, Perrin, P, and Lee, KP. Evidence<br />
for the requirement of T cell costimulation<br />
in the pathogenesis of natural Pneumocystis<br />
carinii pulmonary infection. Microbial Pathogenesis<br />
33:193-201, 2002.<br />
Strbo, N, Yamazaki, K, Lee, KP, Rujkavina, D<br />
and Podack, ER. Heat shock fusion protein<br />
gp96-Ig mediates strong CD8 CTL expansion<br />
in vivo. American Journal of Reproductive Immunology<br />
48:220-25, 2002.<br />
2003<br />
Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and<br />
Harlan, DM. Porcine CD80: cloning, characterization,<br />
and evidence for its role in direct human<br />
T-cell activation. Xenotransplantation 10: 252-<br />
58, 2003.<br />
Lindner. I, Kharfan-Dabaja, M, Ayala. E,<br />
Kolonias, D, Cejas, P, and Lee, KP. Induced differentiation<br />
of chronic myelogenous leukemia to<br />
dendritic cells down-regulates BCR-ABL gene<br />
expression. Journal of Immunology 171:1780-91,<br />
2003.<br />
McCafferty-Grad, J, Bahlis, NJ, Krett, N, Reis, I,<br />
Lee, KP, and Boise, LH. Arsenic trioxide utilizes<br />
caspase dependent and caspase independent<br />
death pathways in myeloma cells. Molecular <strong>Cancer</strong><br />
Therapeutics 2:1155-64, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Direct activation of PKC causes normal human<br />
hematopoietic CD34 + stem cells to differentiate<br />
into DC.<br />
• PKC activation causes many myeloid leukemias<br />
to differentiate into immunologically functional<br />
“leukemic” DC. These cells have potential utility<br />
as “cellular” anti-leukemia vaccines.<br />
• Specific intracellular signaling pathways downstream<br />
of PKC activation control specific aspects<br />
of DC differentiation.<br />
• Arsenic trioxide + ascorbic acid is an effective<br />
combination in the treatment of refractory/relapsed<br />
myeloma.<br />
Bahlis, NJ, McCafferty-Grad, J, Jordan-<br />
McMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,<br />
Eckman, J, Goodman, M, Fernandez, HF, Boise,<br />
LH, and Lee, KP. Feasibility and correlates of<br />
arsenic trioxide combined with ascorbic acid-mediated<br />
depletion of intracellular glutathione for<br />
the treatment of relapsed/refractory multiple myeloma.<br />
Clinical <strong>Cancer</strong> Research 8:3658-68,<br />
2002.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 43
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
STEVEN E. LIPSHULTZ, M.D.<br />
Professor and Chairman of Pediatrics<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lipshultz’s research focuses on the prevention<br />
of cardiomyopathy and heart failure<br />
in children and young adults. He developed<br />
the National Heart, Lung, and Blood Institute<br />
(NHLBI)-sponsored Pediatric Cardiomyopathy<br />
Registry (PCMR) to better understand genetic<br />
and metabolic cardiomyopathies; the NHLBI<br />
P2C2 HIV study to better understand infectious<br />
and inflammatory cardiomyopathies; and the<br />
NCI Dana-Farber <strong>Cancer</strong> Institute childhood<br />
leukemia and NCI Children’s Oncology Group<br />
childhood cancer survivor cohorts to better understand<br />
toxic cardiomyopathies from<br />
anthracycline chemotherapy and mediastinal irradiation.<br />
Further understanding of clinical phenotypes,<br />
human syndrome delineation,<br />
epidemiology, and the natural history of these<br />
pediatric diseases has resulted from these cohorts.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lipshultz, SE, Lipsitz, SR, Sallan, SE, Simbre,<br />
VC 2nd, Shaikh, SL, Mone, SM, Gelber, RD,<br />
and Colan, SD. Long-term enalapril therapy for<br />
left ventricular dysfunction in doxorubicintreated<br />
survivors of childhood cancer. Journal of<br />
Clinical Oncology 20:4517-22, 2002.<br />
Harmon, WG, Dadlani, GH, Fisher, SD, and<br />
Lipshultz, SE. Myocardial and pericardial disease<br />
in HIV. Current Treatment Options in Cardiovascular<br />
Medicine 4:497-509, 2002.<br />
Lipshultz, SE, Giantris, AL, Lipsitz, SR, Kimball,<br />
Dalton V, Asselin, BL, Barr, RD, Clavell, LA,<br />
Hurwitz, CA, Moghrabi, A, Samson, Y, Schorin,<br />
MA, Gelber, RD, Sallan, SE, and Colan, SD.<br />
Doxorubicin administration by continuous infusion<br />
is not cardioprotective: the Dana-Farber 91-<br />
01 Acute Lymphoblastic Leukemia protocol.<br />
Journal of Clinical Oncology 20:1677-82, 2002.<br />
2003<br />
Zareba, KM and Lipshultz, SE . Cardiovascular<br />
complications in patients with HIV infection.<br />
Current Infectious Disease Reports 5:513-20,<br />
2003.<br />
Constine, LS, Hinkle, AS, French, CA,<br />
Kozlowski, AM, Proukou, C, Lipsitz, SR, Miller,<br />
TL, Vermilion, RP, Rifai, N, and Lipshultz, SE.<br />
Radiation-associated risk factors for premature<br />
cardiovascular disease in childhood cancer survivors<br />
include accelerated atherosclerosis. International<br />
Journal of Radiation Oncology Biology<br />
Physics 57(2 Supplement):S199-200, 2003.<br />
Adams, MJ, Lipshultz, SE, Schwartz, C, Fajardo,<br />
LF, Coen, V, and Constine, LS. Radiation-associated<br />
cardiovascular disease: manifestations and<br />
management. Seminars in Radiation Oncology<br />
13:346-56, 2003.<br />
Lipshultz, SE, Fisher, SD, Lai, WW, and Miller,<br />
TL. Cardiovascular risk factors, monitoring, and<br />
therapy for HIV-infected patients. AIDS 17<br />
Supplement 1:S96-122, 2003.<br />
Fisher, SD, Bowles, NE, Towbin, JA, and<br />
Lipshultz, SE. Mediators in HIV-associated cardiovascular<br />
disease: a focus on cytokines and<br />
genes. AIDS 17 Supplement 1:S29-35, 2003.<br />
Lipshultz, SE, Somers, MJ, Lipsitz, SR, Colan,<br />
SD, Jabs, K, and Rifai, N. Serum cardiac troponin<br />
and subclinical cardiac status in pediatric<br />
chronic renal failure. Pediatrics 112:79-86, 2003.<br />
Al-Attar, I, Orav, EJ, Exil, V, Vlach, SA, and<br />
Lipshultz, SE. Predictors of cardiac morbidity<br />
and related mortality in children with acquired<br />
immunodeficiency syndrome. Journal of the<br />
American College of Cardiology 41(9):1598-605,<br />
2003.<br />
Benun, J, Fisher, SD, Orav, EJ, Schwartz, ML,<br />
Exil, V, Messere, C, and Lipshultz, SE . Cardiac<br />
management by pediatricians versus pediatric cardiologists<br />
in an inpatient academic center. American<br />
Heart Journal 145:424-9, 2003.<br />
44<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
Dadlani, GH, Harmon, WG, Simbre II, VC,<br />
Tisma-Dupanovic, S, and Lipshultz, SE .<br />
Cardiomyocyte injury to transplant: pediatric<br />
management. Current Opinion in Cardiology<br />
18:91-7 (Review), 2003.<br />
Adams, MJ, Hardenbergh, PH, Constine, LS,<br />
and Lipshultz, SE . Radiation-associated cardiovascular<br />
disease. Critical Reviews in Oncology/<br />
Hematology 45:55-75 (Review), 2003.<br />
BALAKRISHNA L. LOKESHWAR, PH.D.<br />
Associate Professor of Urology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lokeshwar’s research focuses on the<br />
mechanism of prostate cancer metastasis and<br />
its control by novel chemotherapeutic drugs. For<br />
the last several years, Dr. Lokeshwar’s laboratory<br />
has focused on extracellular matrix degradation<br />
and tumor metastasis. His laboratory has studied<br />
the regulation of a class of basement membrane<br />
matrix degrading enzymes called the matrix<br />
metalloproteinases (MMPs) in prostate cancer.<br />
Using cancer cell cultures established from<br />
human prostate tumor tissues obtained after<br />
prostatectomy, they showed that an imbalance<br />
exists between the levels of MMPs (overproduction)<br />
and their natural inhibitors (underproduction)<br />
in invasive prostate cancer cells. Based on<br />
this finding, they developed a hypothesis that a<br />
novel approach to control metastatic cancer is<br />
to correct the imbalance either by inhibition of<br />
secretion of MMPs or by increasing the extracellular<br />
levels of their endogenous inhibitor.<br />
Since several small synthetic inhibitors of<br />
MMPs exist, they tested the usefulness of the inhibitors<br />
using the criteria of oral bioavailability,<br />
systemic toxicity, and ability to target bone metastasis.<br />
In their search for a suitable inhibitor,<br />
Dr. Lokeshwar’s laboratory tested a series of synthetic<br />
tetracycline analogues, which were shown<br />
to possess a strong anti-collagenase activity with<br />
little or no antibiotic activity. Researchers tested<br />
eight different chemically modified tetracyclines<br />
(CMTs) and found one of them, 6-deoxy, 6-<br />
demethyl, 4-dedimethylamino tetracycline<br />
(CMT-3, COL-3, now termed Metastat R by<br />
CollaGenix Pharmaceuticals, Newtown, Pennsylvania),<br />
to be the most promising. Oral dosing<br />
with this analogue to rats and mice-bearing metastatic<br />
prostate tumors reduced tumor growth and<br />
metastasis, with no measurable systemic toxicity.<br />
Furthermore, prophylactic dosing of animals with<br />
the drug significantly reduced the incidence of<br />
tumor at the site of tumor cell injection. Their<br />
demonstration of a highly antimetastatic and antitumor<br />
activity of CMT-3 in a rat prostate tumor<br />
model led to its phase I clinical trial by the<br />
Developmental Therapeutics Program of the NCI<br />
(NCI-DTP). In the recently concluded human<br />
clinical phase I trial of CMT-3, the NCI-DTP<br />
recommended CMT-3 for phase II and phase III<br />
in patients with soft tissue sarcoma and advanced<br />
metastatic tumors. The University of Miami and<br />
the State University of New York at Stony Brook<br />
have jointly obtained a use patent on this drug.<br />
This finding also has generated a wide interest in<br />
the use of CMT-3 among many investigators<br />
within and outside the University of Miami, including<br />
a new patent issued to the University for<br />
the treatment of corneal ulceration in patients<br />
with meibomian gland disease, also called ocular<br />
rosacea. Dr. Lokeshwar’s current research focuses<br />
on identifying novel plant products that have<br />
been used as folk medicine and identifying novel<br />
combination therapies for advanced hormonerefractive<br />
prostate cancer.<br />
In a related development, COL-3 is undergoing<br />
a phase III clinical trial against HIVinduced<br />
Karposi’s sarcoma. Twenty centers<br />
nationwide are engaged in this trial, headed by<br />
Dr. Bruce DeZube of New England Deaconess<br />
Hospital, Boston.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 45
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
SELECTED PUBLICATIONS<br />
2002<br />
Dursun, D, Wang, M, Monroy, D, Li, DQ,<br />
Lokeshwar, BL , Stern, M, and Pflugfelder, SC.<br />
Experimentally induced dry eye produces ocular<br />
surface inflammation and epithelial disease. Advances<br />
in Experimental Medicine and Biology<br />
506:647-55, 2002.<br />
Dursun, D, Wang, M, Monroy, D, Li, DQ,<br />
Lokeshwar, BL , Stern,ME, and Pflugfelder, SC.<br />
A mouse model of keratoconjunctivitis sicca. Investigative<br />
Ophthalmology & Visual Science<br />
43:632-38, 2002.<br />
Lokeshwar, BL , Selzer, MG, Zhu, BQ, Block,<br />
NL, and Golub, LM. Inhibition of cell proliferation,<br />
invasion, tumor growth and metastasis by<br />
an oral non-antimicrobial tetracycline analog<br />
(COL-3) in a metastatic prostate cancer model.<br />
International Journal of <strong>Cancer</strong> 98:297-309,<br />
2002.<br />
Whitlatch, LW, Young, MV, Schwartz, GG,<br />
Flanagan, JN, Burnstein, KL, Lokeshwar, BL ,<br />
Rich, ES, Holick, MF, and Chen, TC. 25-<br />
Hydroxyvitamin D-1alpha-hydroxylase activity is<br />
diminished in human prostate cancer cells and is<br />
enhanced by gene transfer. Journal of Steroid Biochemistry<br />
and Molecular Biology 81:135-40,<br />
2002.<br />
2003<br />
Chen, TC, Holick, MF, Lokeshwar, BL ,<br />
Burnstein, KL, and Schwartz, GG. Evaluation of<br />
vitamin D analogs as therapeutic agents for prostate<br />
cancer. Recent Results in <strong>Cancer</strong> Research<br />
164:273-88, 2003.<br />
Dandekar, DS, Lokeshwar, VB, Cevallos-<br />
Arellano, E, Soloway, MS, and Lokeshwar, BL .<br />
An orally active Amazonian plant extract (BIRM)<br />
inhibits prostate cancer growth and metastasis.<br />
<strong>Cancer</strong> Chemotherapy and Pharmacology 52:59-<br />
66, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that an imbalance exists between<br />
the levels of MMPs (overproduction) and their<br />
natural inhibitors (underproduction) in invasive<br />
prostate cancer cells.<br />
• Identified a novel, chemically modified nonantimicrobial<br />
tetracycline (CMT-3) as an effective<br />
anti-metastatic drug with potential to treat<br />
prostate cancer metastatic to bone. The NCI<br />
has completed the phase I trial of this drug and<br />
is awaiting further trials. Other novel agents are<br />
being tested in Dr. Lokeshwar’s laboratory, not<br />
only for controlling cancer, but also other<br />
chronic diseases such as chronic ocular surface<br />
inflammation. Dr. Lokeshwar’s research has<br />
brought in one patent to the University of<br />
Miami jointly with the State University of<br />
New York at Stony Brook. Meanwhile, two<br />
patents are pending on the new application of<br />
his research findings.<br />
• Identified a potential application of CMT to<br />
treat the meibomian gland dysfunction that<br />
leads to the ocular rosacea. This was done in<br />
collaboration with Stephen C. Pflugfelder,<br />
M.D., Baylor College of Medicine, Houston,<br />
Texas.<br />
Li de, Q, Shang, TY, Kim, HS, Solomon, A,<br />
Lokeshwar, BL , and Pflugfelder, SC. Regulated<br />
expression of collagenases MMP-1, -8, and -13<br />
and stromelysins MMP-3, -10, and -11 by human<br />
corneal epithelial cells. Investigative Ophthalmology<br />
& Visual Science 44:2928-36, 2003.<br />
46<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
VINATA B. LOKESHWAR, PH.D.<br />
Associate Professor of Urology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lokeshwar’s research focuses on understanding<br />
the mechanism of cancer progression<br />
and tumor angiogenesis. Recent advances in<br />
cancer research have elucidated that the components<br />
of extracellular matrix (ECM) and ECMdegrading<br />
enzymes play a crucial role in<br />
regulating both the metastatic progression of localized<br />
tumors and tumor angiogenesis. Using<br />
bladder and prostate cancer model systems, she<br />
and her colleagues are trying to understand how<br />
ECM affects tumor metastasis and angiogenesis.<br />
Work in Dr. Lokeshwar’s laboratory demonstrates<br />
that an ECM component, hyaluronic acid<br />
(HA, which is a glycosaminoglycan), and its degrading<br />
enzyme, hyaluronidase (HAase), are<br />
closely associated with the biology of cancers of<br />
the bladder and prostate. They observed that elevated<br />
urinary HA and HAase levels are diagnostic<br />
indicators of bladder cancer and its grade,<br />
respectively. This finding has led to the development<br />
of a simple, noninvasive, highly sensitive,<br />
and specific urine test (HA-HAase test; 90 percent<br />
accuracy) for detecting bladder cancer and<br />
monitoring its recurrence.<br />
Dr. Lokeshwar’s research on prostate cancer<br />
showed that immunohistochemical localization<br />
of both HA and HAase in prostate cancer tissues<br />
is greater than 85 percent accurate in predicting<br />
prognosis for prostate cancer patients and is<br />
better than CD44v6 and microvessel density.<br />
Furthermore, both HAase and the HA-HAase<br />
combination are independent predictors of<br />
prognosis. Thus, use of these markers in biopsy<br />
specimens may help clinicians to make individualized<br />
treatment decisions and improve patients’<br />
prognosis.<br />
In their efforts to understand the function of<br />
tumor-derived HAase, the researchers purified<br />
and cloned the first tumor-derived HAase. They<br />
have demonstrated that this tumor-derived<br />
HAase degrades tumor-associated HA into small<br />
angiogenic fragments, which then interact with a<br />
HA receptor, RHAMM, on endothelial cells. The<br />
HA fragments and RHAMM interaction on the<br />
cell surface induces signaling events, resulting in<br />
the stimulation of endothelial cell functions such<br />
as proliferation through the mitogen-activated<br />
protein kinase (MAPK). Endothelial cell proliferation<br />
is of key importance in tumor angiogenesis.<br />
Their recent work, using an antisense cDNA<br />
transfection strategy, demonstrates that tumorderived<br />
HAase is necessary for tumor growth and<br />
muscle invasion of bladder tumors. This is an<br />
important finding since 60 percent of bladder<br />
cancer patients with muscle invasive disease die<br />
within five years.<br />
Currently, Dr. Lokeshwar’s research efforts<br />
focus on the following areas. First, researchers are<br />
comparing the efficacy of the HA-HAase test<br />
with other FDA-approved bladder tumor markers<br />
for monitoring bladder cancer recurrence. Second,<br />
they are testing the potential of HAase and<br />
HA-HAase to predict prognostic potential using<br />
prostate biopsy specimens. Thirdly, they are<br />
investigating the functions of HAase and HAsynthase<br />
enzymes in bladder and prostate cancer<br />
growth and progression.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lokeshwar, VB and Soloway, MS. Re: Urine<br />
based markers of urological malignancy. Journal<br />
of Urology 167:1406-07, 2002.<br />
Lokeshwar, VB , Schroeder, GL, Selzer, MG,<br />
Hautmann, SH, Posey, JT, Duncan, RC, Watson,<br />
R, Rose, L, Markowitz, S, and Soloway, MS.<br />
Bladder tumor markers for monitoring recurrence<br />
and screening comparison of hyaluronic<br />
acid-hyaluronidase and BTA-Stat tests. <strong>Cancer</strong><br />
95:61-72, 2002.<br />
Ekici, S and Lokeshwar, VB . Mesane tumoru<br />
belirleyicileri ve HA-HAase testi. Uroloji Bulteni<br />
13:133-40, 2002.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 47
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
Lokeshwar, VB , Schroeder, GL, Carey, RI,<br />
Soloway, MS, and Iida, N. Regulation of hyaluronidase<br />
activity by alternative mRNA splicing.<br />
Journal of Biological Chemistry 277:33654-63,<br />
2002.<br />
2003<br />
Dandekar, DS, Lokeshwar, VB , Cevallos-<br />
Arellano, E, Soloway, MS, and Lokeshwar, BL.<br />
An orally active Amazonian plant extract (BIRM)<br />
inhibits prostate cancer growth and metastasis.<br />
<strong>Cancer</strong> Chemotherapy and Pharmacology 52:59-<br />
66, 2003.<br />
Simon, MA, Lokeshwar, VB , and Soloway, MS.<br />
Current bladder cancer tests: unnecessary or beneficial?<br />
Critical Reviews in Oncology/Hematology<br />
47:91-107, 2003.<br />
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,<br />
Weed, DT, Fisher, P, and Lokeshwar, VB . Expression<br />
of tumor markers hyaluronic acid and hyaluronidase<br />
(HYAL1) in head and neck tumors.<br />
International Journal of <strong>Cancer</strong> 106:438-45,<br />
2003.<br />
Posey, JT, Soloway, MS, Ekici, S, Sofer, M,<br />
Civantos, F, Duncan, RD, and Lokeshwar, VB.<br />
Evaluation of the prognostic potential of hyaluronidase<br />
activity by alternative mRNA splicing.<br />
Journal of Biological Chemistry 277:33654-63,<br />
2002.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Developed the HA-HAase urine test, a noninvasive<br />
test that is about 90 percent accurate<br />
in detecting bladder cancer and monitoring its<br />
recurrence.<br />
• Established that HA and HAase are greater than<br />
85 percent accurate prognostic indicators for<br />
prostate cancer.<br />
• Demonstrated the function of tumor-derived<br />
HAase in bladder tumor growth and muscle<br />
invasion.<br />
IZIDORE LOSSOS, M.D.<br />
Associate Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
By examining gene expression profiles in diffuse<br />
large B-cell lymphomas (DLBCL) and<br />
applying a pattern recognition algorithm-termed<br />
hierarchical clustering, Dr. Lossos’ laboratory<br />
identified at least two molecularly distinct forms<br />
of the disease. These were defined by specific<br />
gene expression signatures: germinal center (GC)<br />
B cell-like DLBCL characterized by expression of<br />
genes normally expressed in GC B cells, and having<br />
a significantly better overall survival than the<br />
activated B cell (ABC)-like DLBCL characterized<br />
by expression of genes normally induced during<br />
in vitro activation of B cells. Discovery of new<br />
DLBCL tumor categories with distinct outcomes<br />
by gene expression data suggested that<br />
lymphomagenesis mechanisms involved in the<br />
establishment or progression of these tumors may<br />
be distinct. Indeed, researchers in this laboratory<br />
and others have demonstrated that: 1) the<br />
t(14;18)(q32;q21) translocation involving the<br />
bcl-2 gene and the amplification of the c-rel locus<br />
on chromosome 2p are detected exclusively in<br />
GCB-like DLBCL; 2) the mutational machinery<br />
introducing somatic mutations into Ig genes is<br />
active in all GCB-like DLBCL but not in the majority<br />
of ABC-like DLBCL tumors, and 3) the<br />
ABC-like DLBCL cell lines demonstrate high<br />
expression of NF-κB target genes and have constitutive<br />
activity of I-κB kinase complex (IKK)<br />
that is not observed in the GCB-like DLBCL cell<br />
lines. Inhibition of IKK by dominant negative<br />
forms of IκKβ was cytotoxic to ABC-like but not<br />
to GCB-like DLBCL cell lines. The latter study<br />
demonstrated that NF-κB pathway is a potential<br />
new therapeutic target in ABC-like DLBCL.<br />
However, specific pathways active in GCB-like<br />
DLBCL have not yet been characterized.<br />
Analysis of the relative prognostic contribution<br />
of the individual genes comprising the expression<br />
signatures defining these two DLBCL<br />
subgroups demonstrated that expression of only<br />
48<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
some of these genes significantly correlates with<br />
DLBCL survival. An expressed sequence tag (EST)<br />
that the laboratory named human germinal<br />
center-associated lymphoma (HGAL) (UniGene<br />
cluster 49614 -Clone 814622,GI:2210537) was<br />
identified as a best predictor of DLBCL survival.<br />
The predictive power of HGAL was International<br />
Prognostic Indicator (IPI) independent, as demonstrated<br />
by multivariate analysis including components<br />
of the IPI. Furthermore, the prognostic<br />
power of HGAL expression in predicting survival<br />
was also shown when its expression was considered<br />
as a continuous variable demonstrating<br />
direct correlation between higher levels of its<br />
expression and longer survival. Higher HGAL<br />
expression in ABC-like DLBCL still predicted<br />
better overall survival. There was no difference in<br />
the complete response rates between patients with<br />
high and low HGAL expression, thus suggesting<br />
that high HGAL expression was associated with<br />
either better response to salvage treatment or<br />
lower relapse rates due to more complete tumor<br />
cell eradication or effective immunological<br />
surveillance.<br />
The laboratory has cloned the full-length<br />
cDNA of this EST from both sorted GC lymphocytes<br />
and from the Ramos cell line and<br />
termed the gene human germinal center-associated<br />
lymphoma (HGAL) (GenBank accession<br />
number AF521911). HGAL is located on chromosome<br />
3q13. Comparison of the genomic sequence<br />
to the cDNA sequence revealed that<br />
HGAL spans 11kb. Recognition of a Kozak sequence<br />
and search for the longest open reading<br />
frame (ORF) led to the identification of a putative<br />
ORF extending from exon 1 to exon 6 and<br />
encoding a 178 amino acid protein, with 51 percent<br />
identity to the murine M17 protein that is<br />
expressed in GC lymphocytes. The HGAL gene<br />
product had a hydrophilic profile with no predicted<br />
transmembrane domain and lacked a nuclear localization<br />
sequence. HGAL contains a modified<br />
immunoreceptor tyrosine-based activation motif<br />
termed ITAM (D/EX 7<br />
D/EX 2<br />
YX 2<br />
LX 7<br />
YX 2<br />
L) that<br />
plays a role in signal transduction in B and T<br />
lymphocytes. HGAL is not expressed in nonlymphoid<br />
tissues but is expressed at high levels<br />
only in GC lymphocytes, at intermediate levels in<br />
memory B cells, and at relatively low levels in<br />
peripheral blood B cells. In tumors, its expression<br />
is high in follicular lymphoma tumors, low in<br />
chronic lymphocytic leukemia cells, and heterogeneous<br />
in DLBCL specimens. Thus, HGAL expression<br />
may correlate with specific stages of<br />
B-cell differentiation, especially the GC stage.<br />
The function of HGAL in normal lymphocytes<br />
and the reason its expression in DLBCL<br />
correlates with better DLBCL outcome, are<br />
not known. Whether the improved survival of<br />
patients with high HGAL-content tumors is<br />
attributed to specific function of this gene or<br />
is a marker of important biologic characteristic<br />
of the tumor is unknown. Researchers in Dr.<br />
Lossos’ laboratory are currently investigating<br />
these questions.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lossos, IS , Or, R, Ginzburg, V, Christensen,<br />
TG, Mashriki, Y, and Breuer, R. Cyclosporin<br />
A upmodulates bleomycin-induced pulmonary<br />
fibrosis in BALB/c mice. Respiration 69:344-49,<br />
2002.<br />
Auffermann-Gretzinger, S, Lossos, IS , Vayntrub,<br />
TA, Leong, W, Grumet, FC, Blume, KG,<br />
Stockerl-Goldstein, KE, Levy, R, and Shizuru,<br />
JA. Rapid establishment of dendritic cell chimerism<br />
in allogeneic hematopoietic cell transplant<br />
recipients. Blood 99:1442-48, 2002.<br />
Bokstein, F, Lossos, A, Lossos, IS, and Siegal, T.<br />
Central nervous system relapse of systemic non-<br />
Hodgkin’s lymphoma: results of treatment based<br />
on high-dose methotrexate combination chemotherapy.<br />
Leukemia & Lymphoma 43:587-93,<br />
2002.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 49
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
Huang, JZ, Sanger, WG, Greiner, TC, Staudt,<br />
LM, Weisenburger, DD, Pickering, DL, Lynch,<br />
JC, Armitage, JO, Warnke, RA, Alizadeh, AA,<br />
Lossos, IS , Levy, R, and Chan, WC. The<br />
t(14;18) defines a unique subset of diffuse large<br />
B-cell lymphoma with a germinal center B-cell<br />
gene expression profile. Blood 99:2285-90, 2002.<br />
Lossos, IS , Thorstenson, YR, Wayne, TL, Oefner,<br />
PJ, Levy, R, and Chu, G. Mutation of the ATM<br />
gene is not involved in the pathogenesis of either<br />
follicle center lymphoma or its transformation to<br />
higher-grade lymphoma. Leukemia & Lymphoma<br />
43:1079-85, 2002.<br />
Lossos, IS , Alizadeh, AA, Diehn, M, Warnke, R,<br />
Thorstenson, Y, Oefner, PJ, Brown, PO,<br />
Botstein, D, and Levy, R. Transformation of follicular<br />
lymphoma to diffuse large-cell lymphoma:<br />
Alternative patterns with increased or decreased<br />
expression of c-myc and its regulated genes. Proceedings<br />
of the National Academy of Sciences<br />
USA 99:8886-91, 2002.<br />
Lossos, IS , Warnke, R, and Levy, R. BCL-6<br />
mRNA expression in higher grade transformation<br />
of follicle center lymphoma: correlation with somatic<br />
mutations in the 5' regulatory region of the<br />
BCL-6 gene. Leukemia 16:1857-62, 2002.<br />
Lossos, IS , Natkunam, Y, Levy, R, and Lopez,<br />
CD. Apoptosis stimulating protein of p53<br />
(ASPP2) expression differs in diffuse large B-cell<br />
and follicular center lymphoma: correlation with<br />
clinical outcome. Leukemia & Lymphoma<br />
43:2309-17, 2002.<br />
2003<br />
Lossos, IS , Alizadeh, AA, Rajapaksa, R,<br />
Tibshirani, R, and Levy, R. HGAL is a novel<br />
interleukin-4-inducible gene that strongly predicts<br />
survival in diffuse large B-cell lymphoma.<br />
Blood 101:433-40, 2003.<br />
Lossos, IS , Czerwinski, DK, Wechser, MA, and<br />
Levy, R. Optimization of quantitative real-time<br />
RT-PCR parameters for the study of lymphoid<br />
malignancies. Leukemia 17:789-95, 2003.<br />
Martinez-Climent, JA, Alizadeh, AA, Segraves, R,<br />
Blesa, D, Rubio-Moscardo, F, Albertson, DG,<br />
Garcia-Conde, J, Dyer, MJ, Levy, R, Pinkel, D,<br />
and Lossos, IS . Transformation of follicular lymphoma<br />
to diffuse large cell lymphoma is associated<br />
with a heterogeneous set of DNA copy<br />
number and gene expression alterations. Blood<br />
101:3109-17, 2003.<br />
Akasaka, T, Lossos, IS , and Levy, R. BCL6 gene<br />
translocation in follicular lymphoma: a harbinger<br />
of eventual transformation to diffuse aggressive<br />
lymphoma. Blood 102:1443-48, 2003.<br />
Lossos, IS and Levy, R. Diffuse large B-cell lymphoma:<br />
insights gained from gene expression profiling.<br />
International Journal of Hematology<br />
77:321-29, 2003.<br />
Lossos, IS and Levy, R. Higher grade transformation<br />
of follicular lymphoma: phenotypic tumor<br />
progression associated with diverse genetic lesions.<br />
Seminars in <strong>Cancer</strong> Biology 13:191-202,<br />
2003.<br />
Lossos, IS , Akasaka, T, Martinez-Climent, JA,<br />
Siebert, R, and Levy, R. The BCL6 gene in B-cell<br />
lymphomas with 3q27 translocations is expressed<br />
mainly from the rearranged allele irrespective of<br />
the partner gene. Leukemia 17:1390-97, 2003.<br />
Do, B, Lossos, IS , Thorstenson, Y, Oefner, PJ,<br />
and Levy, R. Analysis of FAS (CD95) gene mutations<br />
in higher-grade transformation of follicle<br />
center lymphoma. Leukemia & Lymphoma<br />
44:1317-23, 2003<br />
Lossos, IS , Akasaka, T, and Levy, R. Multiple<br />
BCL6 translocation partners in individual cases<br />
of gastric lymphoma. Blood 102:1931-32, 2003.<br />
50<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
CLARA MILIKOWSKI, M.D.<br />
Associate Professor of Pathology<br />
DESCRIPTION OF RESEARCH<br />
Since 1993, the Cooperative Breast <strong>Cancer</strong><br />
Tissue Resource (CBCTR) has provided<br />
breast cancer tissue to researchers for the study of<br />
clinical markers of tumor prognosis and the<br />
evaluation of promising diagnostic tests based on<br />
these markers. It is a centrally administered repository<br />
of archival breast cancer tissues with associated<br />
clinical and outcome data to meet this<br />
need, and it is comprised of four sites in the<br />
United States—the University of Miami, Fox<br />
Chase <strong>Cancer</strong> <strong>Center</strong>, Kaiser-Permanente (Portland,<br />
Oregon), and Washington University (St.<br />
Louis, Missouri). These four institutions are geographically<br />
dispersed, offer significantly different<br />
clinical resources to the CBCTR, and have gathered<br />
their breast cancer cases from widely different<br />
clinical settings, which together parallel SEER<br />
data for breast cancer.<br />
Each site identified, segregated, and cataloged<br />
the specimens for the CBCTR locally. Selected<br />
clinical and outcome data obtained from<br />
its local hospital tumor registry are associated<br />
with each case. The combined clinical and outcome<br />
data from all four sites, stored centrally by<br />
Information Management Services (IMS), in addition<br />
to the tissue specimens stored at each site,<br />
constitute the “virtual tissue resource” of the<br />
CBCTR. IMS has used this material to prepare a<br />
searchable database for the CBCTR online, at<br />
http://www-cbctr.ims.nci.nih.gov/. Here, investigators<br />
can search the CBCTR material to determine<br />
if the specimens are adequate for use in<br />
their research. If investigators feel the resource<br />
meets their needs, instructions for application for<br />
these tissues are available on the same web site.<br />
The CBCTR currently has a “progression<br />
array,” which was designed by an NCI statistician<br />
who calculated the type and number of specimens<br />
that would be required to produce an array<br />
whose statistical power had already been calculated.<br />
Each of the sites has contributed to this<br />
[tissue micro-] array.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Regev, A, Berho, M, Jeffers, LJ, Milikowski, C,<br />
Molina, EG, Pyrsopoulos, NT, Feng, ZZ, Reddy,<br />
KR, and Schiff, ER. Sampling error and<br />
intraobserver variation in liver biopsy in patients<br />
with chronic HCV infection. American Journal<br />
of Gastroenterology 97:2614-18, 2002.<br />
2003<br />
Abdel-Wahab, M, Krishan, A, Milikowski, C,<br />
Abdel-Wahab, A., Walker, G, and Markoe, A.<br />
Androgen receptor antigen density and S-phase<br />
fraction in prostate cancer: a pilot study. Prostate<br />
<strong>Cancer</strong> and Prostatic Diseases 6:294-300, 2003.<br />
Fishman, JE, Milikowski, C, Ramsinghani, R,<br />
Velasquez, MV, and Aviram, G. US-guided coreneedle<br />
biopsy of the breast: how many specimens<br />
are necessary? Radiology 226:779-82, 2003.<br />
Pasquale, M and Milikowski, C . Three millimeter<br />
apocrine adenoma in a man: Case report and<br />
review of the literature. Archives of Pathology &<br />
Laboratory Medicine 127:1498-500, 2003.<br />
LUIS E. RAEZ, M.D., F.A.C.P.<br />
Assistant Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Raez’s research focuses on translational<br />
research in the areas of lung cancer, head<br />
and neck cancer, and the development of clinical<br />
trials with novel compounds for these diseases.<br />
Dr. Raez is the principal investigator in two<br />
phase-I trials that are developing allogeneic tumor<br />
cancer vaccines for lung cancer patients<br />
(both of them engineered at the University of<br />
Miami by Eckhard R. Podack, M.D., Ph.D.).<br />
Now that the first trial with the co-stimulatory<br />
molecule B7.1 (CD 80) has been successfully<br />
completed, he has developed a phase II clinical<br />
trial with the same vaccine to vaccinate patients<br />
with minimal disease with the goal to prevent<br />
relapse. Patients treated in the first phase I clini-<br />
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cal trial with the B7.1 vaccine were incurable and<br />
had an expected survival of less than six months.<br />
Due to the therapy, however, 30 percent of the<br />
patients achieved disease stabilization or response<br />
and at least three patients now have survived for<br />
more than two years, with a median survival of<br />
18 months for the whole group. Dr. Raez will<br />
begin the phase I trial with the allogeneic tumor<br />
vaccine gp-96 for patients with lung cancer soon<br />
after FDA approval. This vaccine is more immunogenic<br />
than the B7.1 used before. In mice, it<br />
has been shown to have a stronger immune response.<br />
Due to his gp-96 vaccine project and the<br />
success of the B7.1 vaccine, Dr. Raez was granted<br />
a “Research Career Development Award” in 2002<br />
by the American Society of Clinical Oncology<br />
(ASCO) with funds to support his research for<br />
three years.<br />
Dr. Raez and his colleagues recently received<br />
<strong>Cancer</strong> Therapy Evaluation Program (CTEP)<br />
approval for a phase I clinical trial with a new<br />
drug called cytochlor (NSC 371331), a potent<br />
radiation sensitizer, which was discovered by<br />
Sheldon Greer, Ph.D., at the University of Miami.<br />
Dr. Raez and Dr. Greer will treat patients<br />
with radiation therapy with the goal to improve<br />
response and prevent relapse. Dr. Raez also was<br />
awarded the 2002-2003 Stanley J. Glaser Foundation<br />
Biomedical Research Award and funding<br />
for the cytochlor project. Additionally, CTEP has<br />
approved the project and will provide funding<br />
and drug production for its development.<br />
Dr. Raez also works with Theodore J.<br />
Lampidis, Ph.D., in developing the first phase I<br />
trial in humans with the combination of 2-DG<br />
with chemotherapy. 2-DG has a novel mechanism<br />
of action focused in the destruction of slowgrowing<br />
cells in the core of the tumors where<br />
conventional chemotherapy and radiation have<br />
not worked, which already has been proven by<br />
Dr. Lampidis’ research. Dr. Raez also has been<br />
trying to find the prognostic role of c-Kit, Bag-1,<br />
and CEACAM-1 in lung cancer, trying to correlate<br />
it with clinical responses and survival.<br />
Dr. Raez also has initiated several important<br />
clinical trials with new compounds for lung and<br />
head and neck cancers with Cpt-11, oxaliplatin,<br />
capecitabine, and Velcade, among others.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Santos, ES, Raez, LE, Salvatierra, J,<br />
Morgensztern, D, Shanmugan, N, and Neff, GW.<br />
Primary hepatic non-Hodgkin’s lymphomas: a<br />
case report and review of the literature. American<br />
Journal of Gastroenterology (Review) 98:2789-<br />
93, 2003.<br />
Raez LE, Cassileth, PA, Schlesselman, JJ,<br />
Padmanabhan, S, Fisher, EZ, Baldie, PA, Sridhar,<br />
K, and Podack , ER. Induction of CD8 T-cell-Ifngamma<br />
response and positive clinical outcome<br />
after immunization with gene-modified allogeneic<br />
tumor cells in advanced non-small-cell lung<br />
carcinoma. <strong>Cancer</strong> Gene Therapy 10:850-58,<br />
2003.<br />
Santos, ES, Raez, LE, Kharfan-Dabaja, MA,<br />
Angulo, J, Restrepo, A, and Byrnes, JJ. Survival<br />
of renal allograft following de novo hemolytic<br />
uremic syndrome after kidney transplantation.<br />
Transplantation Proceedings 35:1370-74, 2003.<br />
52<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
CAIO MAX S. ROCHA LIMA, M.D.<br />
Associate Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Rocha Lima’s research focuses on developing<br />
novel treatments in patients with cancer<br />
(mainly lung cancer and gastrointestinal malignancies).<br />
Researchers in his laboratory work to identify<br />
prognostic factors in patients with cancer.<br />
They also are cooperating in the development of<br />
molecular finger-printing for gastrointestinal cancer<br />
patients. They are studying 33,000 genes in<br />
pancreatic cancer and colorectal cancer as an attempt<br />
to identify different gene expression patterns<br />
(tumor phenotype) and their correlation<br />
with overall survival, benefit to different types of<br />
treatment, and tumor aggressiveness. The investigators<br />
also are working to identify chromosomes<br />
alleles related to drug metabolism from buffy coat<br />
(leucocytes) and correlating with chemotherapy<br />
toxicity.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Rocha Lima, CM, Herndon, JE 2nd, Kosty, M,<br />
Clamon, G, and Green, MR. Therapy choices<br />
among older patients with lung carcinoma: an<br />
evaluation of two trials of the <strong>Cancer</strong> and Leukemia<br />
Group B. <strong>Cancer</strong> 94:181-87, 2002.<br />
Rocha Lima, CM, Savarese, D, Bruckner, H,<br />
Dudek, A, Eckardt, J, Hainsworth, J, Yunus, F,<br />
Lester, E, Miller, W, Saville, W, Elfring, GL,<br />
Locker, PK, Compton, LD, Miller, LL, and<br />
Green, MR. Irinotecan plus gemcitabine induces<br />
both radiographic and CA 19-9 tumor marker<br />
responses in patients with previously untreated<br />
advanced pancreatic cancer. Journal of Clinical<br />
Oncology 20:1182-91, 2002.<br />
Rocha Lima, CM and Centeno, B. Update on<br />
pancreatic cancer. Current Opinion in Oncology<br />
14:424-30, 2002.<br />
Rocha Lima, CM and Joppert, MG.<br />
Topoisomerase I-based nonplatinum combinations<br />
in non-small-cell lung cancer. Oncology<br />
(Huntington) 16:25-31, 2002.<br />
Freitas, JR and Rocha Lima, CM. Therapy of<br />
advanced non-small-cell lung cancer with<br />
irinotecan and gemcitabine in combination.<br />
Clinical Lung <strong>Cancer</strong> 4 (Supplement 1): S26-90,<br />
2002.<br />
2003<br />
Coutinho, AK and Rocha Lima, CM. Metastatic<br />
colorectal cancer: systemic treatment in the new<br />
millennium. <strong>Cancer</strong> Control 10:224-38, 2003.<br />
Rocha Lima, CM and Chiappori, A. Treatment<br />
of relapsed small-cell lung cancer—a focus on the<br />
evolving role of topotecan. Lung <strong>Cancer</strong> 40:229-<br />
36, 2003.<br />
Bhargava, P, Jani, CR, O’Donnel, JL, Stuart, KE,<br />
and Rocha Lima, CM. Gemcitabine and<br />
irinotecan in locally advanced or metastatic<br />
biliary cancer. Oncology 17: 23-26, 2003.<br />
Chiappori, AA and Rocha Lima, CM. New<br />
agents in the treatment of small-cell lung cancer:<br />
focus on gemcitabine. Clinical Lung <strong>Cancer</strong> 4<br />
(Supplement 2): S56-63, 2003.<br />
Simon, GR, Ruckdeschel, JC, Williams, C, Cantor,<br />
A, Chiappori, A, Rocha Lima, CM, Antonia<br />
S, Haura, E, Wagner, H, Robinson, L, Sommers,<br />
E, Alberts, M, and Bepler, G. Gefitinib (ZD1839)<br />
in previously treated advanced non-small-cell<br />
lung cancer: experience from a single institution.<br />
<strong>Cancer</strong> Control 10:388-95, 2003.<br />
Rocha Lima, CM, Leong, SS, Sherman, CA,<br />
Perkel, JA, Putman, T, Safa, AR, and Green, MR.<br />
Irinotecan and gemcitabine in patients with solid<br />
tumors: phase I trial. Oncology (Huntington)<br />
16:19-24, 2002.<br />
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HIGHLIGHTS/DISCOVERIES<br />
Novel treatments with the following agents were<br />
designed and tested clinically by Dr. Rocha Lima:<br />
• IrinoGem (gemcitabine and irinotecan in combination)<br />
for pancreatic cancer and lung cancer<br />
(both small and non-small cell lung cancer).<br />
• DocGem in lung cancer.<br />
• ETopoTax in small cell lung cancer.<br />
His clinical efforts with the agent IrinoGem<br />
resulted in establishing it as a new clinical treatment<br />
option for pancreatic cancer.<br />
JOSEPH D. ROSENBLATT, M.D.<br />
Professor of Medicine and<br />
Division Chief of Hematology-Oncology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Rosenblatt’s research focuses on the development<br />
of novel immune therapy and gene<br />
therapy strategies for cancer. Current research has<br />
focused on the potential role of recruitment of<br />
immune effector cells, using the local elaboration<br />
of both constitutive and inflammatory chemokines,<br />
such as secondary lymphoid chemokine (SLC),<br />
DC-CK1 and/or RANTES respectively, on the<br />
development of an anti-tumor response. Chemokine<br />
delivery has been investigated alone, or in combination<br />
with, expression of the costimulatory ligands<br />
CD80 (B7.1) or CD40L. Several delivery strategies<br />
have been investigated including the use of retroviral<br />
vectors, and/or the use of herpes simplex virus (HSV)<br />
amplicon vectors in several murine tumor models.<br />
Preliminary results suggest that the recruitment<br />
of naïve T cells using SLC is a particularly effective<br />
means of enhancing the anti-tumor immune<br />
response, particularly when combined with CD40Linduced<br />
co-stimulation. This strategy is being<br />
formally investigated using the OT-1 transgenic<br />
mouse model, which has a constitutively expressed<br />
T-cell receptor with defined anti-ovalbumin specificity<br />
and the murine tumors expressing the target<br />
ovalbumin antigen, for effects on tumor-induced<br />
tolerance and the development of systemic immunity.<br />
In a separate effort, the utility of HSV-derived<br />
helper virus-free amplicons is being tested<br />
for efficacy in augmenting the immunogenicity<br />
and antigen-presenting capability of fresh chronic<br />
lymphocytic leukemia cells (CLL). Both CD40L<br />
and CD80, and/or the tumor necrosis factor (TNF)<br />
ligand family member LIGHT have been targeted<br />
to fresh CLL cells using the helper free HSV<br />
amplicons. Results suggest the augmented ability<br />
of such CLL cells to present antigen in an allogeneic<br />
mixed-lymphocyte-tumor cell reaction, and/<br />
or to serve as stimulatory cells for the derivation<br />
of autologous cytolytic T cells in vitro without<br />
deleterious effects on MHC-I expression is seen<br />
with HSV helper virus-containing preparations.<br />
A novel means of immune effector molecule<br />
delivery, which combines the antigen binding<br />
capabilities and localization characteristics of antibodies<br />
with the local delivery of a co-stimulatory<br />
molecule, anti-angiogenic peptide, or a chemokine,<br />
also is under investigation. Antibody fusion<br />
proteins targeting the human breast and ovarian<br />
cancer her2/neu antigen, linked to the extracellular<br />
domains of the B7.1 and/or 41BB-L<br />
costimulatory ligands, have been synthesized and<br />
their in vitro ability to bind to cognate antigenic<br />
targets and to deliver a local co-stimulatory signal<br />
has been documented. Additional fusions currently<br />
being developed in the laboratory include<br />
fusion of the anti-angiogenic peptide endostatin<br />
to anti-her2/neu antibody sequences, as well as<br />
fusion of the inflammatory chemokine RANTES.<br />
Selective targeting of immune effector cells using<br />
both local chemokine vector administration or<br />
antibody-fusion protein administration is being<br />
evaluated further.<br />
A novel antibody-fusion that targets delivery<br />
of endostatin to the site of her2/neu-expressing<br />
tumors has also been synthesized in collaboration<br />
with Seung-Uon Shin, M.D., and shows excellent<br />
efficacy in preclinical models. This fusion appears<br />
to substantially improve the results obtained with<br />
either antibody or endostatin alone.<br />
Currently, Dr. Rosenblatt’s laboratory is<br />
studying efficacy using a novel B-cell deficient<br />
mouse model, which allows testing of antibody<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
fusion protein targeting to xenogeneic (e.g., CEA,<br />
her2/neu) antigens, while preserving T-cell<br />
immune-effector functions. The B-cell deficient<br />
model also has demonstrated T-cell responses to<br />
tumor and may be better than those seen in the<br />
immunocompetent mouse. The laboratory is<br />
currently investigating the reasons for altered<br />
responses in the absence of B cells, and the possibility<br />
of applying this approach to clinically using<br />
antibody depletion of B cells with rituximab.<br />
Dr. Rosenblatt and his colleagues also have<br />
collaborated with the laboratory of Vicente<br />
Planelles, Ph.D., at the University of Utah, on<br />
developing several new approaches to HIV-1 gene<br />
therapy. These include the use of mutated tRNA LYS3<br />
primers, which can anneal to the sequences other<br />
than primer-binding sequences on the HIV-1<br />
genome, or tRNA LYS3 mutated in adenosine residue<br />
A58, which prevents normal methylation of<br />
the adenosine residue and disrupts proper termination<br />
of the nascent reverse transcript, thereby<br />
inhibiting completion of HIV-1 reverse transcription<br />
in model systems. Other investigations have<br />
centered on the effects of defective HIV-1 derived<br />
vectors on HIV-1 spread in culture. Recent experiments<br />
have demonstrated that efficient trafficking<br />
of defective HIV-1 vectors is observed<br />
in vitro following superinfection with wild type<br />
HIV-1 and that such trafficking results in a<br />
marked inhibition of wild type viral spread.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lancet, JE, Rosenblatt, JD , and Karp, JE.<br />
Farnesyltransferase inhibitors and myeloid malignancies:<br />
phase I evidence of Zarnestra activity in<br />
high-risk leukemias. Seminars in Hematology<br />
39:31-35, 2002.<br />
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,<br />
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,<br />
JD. Herpes simplex virus (HSV) amplicon-mediated<br />
codelivery of secondary lymphoid tissue<br />
chemokine and CD40L results in augmented antitumor<br />
activity. <strong>Cancer</strong> Research 62:6545-51,<br />
2002.<br />
Rosenblatt, JD , Shin, SU, Nechustan, H, Yi,<br />
KH, and Tolba, K. Potential role of chemokines<br />
in immune therapy of cancer. Israel Medical Association<br />
Journal 4:1054-59, 2002.<br />
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,<br />
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD .<br />
HSV amplicon-mediated delivery of LIGHT enhances<br />
the antigen-presenting capacity of chronic<br />
lymphocytic leukemia. Molecular Therapy 6:455-<br />
63, 2002.<br />
Andela, VB, Rosenblatt, JD , Schwarz, EM,<br />
Puzas, EJ, O’Keefe, RJ, and Rosier, RN. Synergism<br />
of aminobisphosphonates and farnesyl<br />
transferase inhibitors on tumor metastasis. Clinical<br />
Orthopaedics 397:228-39, 2002.<br />
2003<br />
Khorana, AA, Rosenblatt, JD , Sahasrabudhe,<br />
DM, Evans, T, Ladrigan, M, Marquis, D, Rosell,<br />
K, Whiteside, T, Phillippe, S, Acres, B, Slos, P,<br />
Squiban, P, Ross, M, and Kendra, K. A phase I<br />
trial of immunotherapy with intratumoral adenovirus-interferon-gamma<br />
(TG1041) in patients<br />
with malignant melanoma. <strong>Cancer</strong> Gene Therapy<br />
10:251-9, 2003.<br />
Andela, VB, Pirri, M, Schwarz, EM, Puzas, EJ,<br />
O’Keefe, RJ, Rosenblatt, JD, and Rosier, RN.<br />
The mevalonate synthesis pathway as a therapeutic<br />
target in cancer. (Review) Clinical Orthopaedics<br />
415 (Supplement):S59-66, 2003.<br />
Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A,<br />
Lu, C, McNair, C, Abboud, CN, and Rosenblatt,<br />
JD. Effects of the farnesyl transferase inhibitor<br />
R115777 on normal and leukemic hematopoiesis.<br />
Leukemia 17:1806-12, 2003.<br />
Rosenblatt, JD and Harrington, WJ Jr. Leukemia<br />
and myelopathy: the persistent mystery of pathogenesis<br />
by HTLV-I/II. <strong>Cancer</strong> Investigation<br />
21:323-24, 2003.<br />
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HIGHLIGHTS/DISCOVERIES<br />
• Developed novel antibody-chemokine and antibody-costimulatory<br />
ligand fusion proteins with<br />
dual function and preserved targeting capabilities.<br />
• Developed a novel strategy for gene therapy of<br />
HIV-1 using mutations introduced into the<br />
tRNA LYS3 primer.<br />
• Demonstrated the potential role for HSV<br />
amplicon vectors in gene therapy of malignancy,<br />
particularly CLL.<br />
• Demonstrated the use of trafficking and inhibition<br />
by defective HIV-1 as a novel approach to<br />
HIV-1 gene therapy.<br />
• Demonstrated the utility of combining<br />
chemokine delivery with costimulatory ligands<br />
in augmenting mouse response to tumors.<br />
NIRAMOL SAVARAJ, M.D.<br />
Adjunct Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Molecular Mechanism of Drug Resistance in<br />
Small Cell Lung <strong>Cancer</strong><br />
Small cell lung cancer (SCLC) usually responds<br />
to chemotherapy, but relapse is inevitable. Although<br />
several new chemotherapeutic agents have<br />
shown activity in SCLC, salvage therapy is still<br />
poor. Research in Dr. Savaraj’s laboratory focuses<br />
on identifying the mechanisms of drug resistance<br />
in SCLC and developing approaches to overcome<br />
them.<br />
Since the combination of VP-16 and<br />
cisplatin is the most commonly used regimen in<br />
treating SCLC, the laboratory has studied the<br />
mechanism(s) of resistance of these two agents.<br />
They have established two pairs of cisplatin resistant<br />
sublines (SR-2 and BC), one VP-16 resistant<br />
subline (BV), one MRP1 (SCLCA), and one P-<br />
gp (SCLCR) resistant subline from two parental<br />
lines (SCLC1 and SCLCB). These cell lines were<br />
used to study the mechanism(s) of resistance in<br />
SCLC. Using cDNA subtraction and microarray,<br />
the laboratory has found that both cisplatin resistant<br />
cell lines overexpressed three families of<br />
cDNAs, the MMP family, DNA damage and repair<br />
proteins, and proteins involved in translation.<br />
The specific genes that were consistently<br />
elevated were elongation factor and ribosomal<br />
protein. Since rapamycin or its analog CCI-779<br />
can inhibit translation of the mRNA encoding<br />
elongation factor, they have investigated whether<br />
these analogs could reverse cisplatin drug resistance.<br />
Dr. Savaraj and her colleagues found that<br />
all cell lines were sensitive to rapamycin and<br />
CCI-779 with the ID 50<br />
ranged from 0.05-0.1µg/<br />
ml. Furthermore, at 0.01µg/ml both drugs could<br />
also restore cisplatin sensitivity, and could completely<br />
restore VP-16 sensitivity in BV cell line.<br />
Neither rapamycin nor CCI-779 is able to reverse<br />
P-gp1 or MRP1 resistance.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Feun, LG, Modiano, M, Lee, K, Mao, J, Marini,<br />
A, Savaraj, N, Plezia, P, Almassian, B, Colacino,<br />
E, Fischer, J, and MacDonald, S. Phase I and<br />
pharmacokinetic study of 3-aminopyridine-2-<br />
carboxaldehyde thiosemicarbazone (3-AP) using a<br />
single intravenous dose schedule. <strong>Cancer</strong> Chemotherapy<br />
and Pharmacology 50:223-29, 2002.<br />
Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG,<br />
Xu, R, Xu, J, and Savaraj, N. Procollagen-like<br />
protein as a molecular target in the treatment of<br />
primary brain tumor. ScientificWorldJournal.<br />
2:125-26, 2002.<br />
Feun, LG, Savaraj, N, Hurley, J, and Marini, A.<br />
Phase II trial of Paclitaxel and Dacarbazine with<br />
filgrastim administration in advanced malignant<br />
melanoma. <strong>Cancer</strong> Investigation 20:357-61,<br />
2002.<br />
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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M<br />
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ.<br />
Hypoxia increases tumor cell sensitivity to glycolytic<br />
inhibitors: a strategy for solid tumor therapy<br />
(Model C). Biochemical Pharmacology 64:1745-<br />
51, 2002.<br />
2003<br />
Feun, LG, O’Brien, C, Molina, E, Rodriguez, M,<br />
Jeffers, L, Schiff, ER, Marini, A, Savaraj, N, and<br />
Ardalan, B. Recombinant leukocyte interferon,<br />
doxorubicin, and 5FUDR in patients with hepatocellular<br />
carcinoma-A phase II trial. Journal of<br />
<strong>Cancer</strong> Research and Clinical Oncology 129:17-<br />
20, 2003.<br />
Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L,<br />
Donnelly, E, Solomon, J, Sundaram, M, Feun, L,<br />
and Savaraj, N. Phase II study of vinorelbine<br />
with low dose prednisone in the treatment of<br />
hormone-refractory metastatic prostate cancer.<br />
Oncology Report 10:885-89, 2003.<br />
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,<br />
Lampidis, TJ, Robles, C, Furst, AJ, and Feun,<br />
LG. Overexpression of mutated MRP4 in<br />
cisplatin resistant small cell lung cancer cell line:<br />
Collateral sensitivity to azidothymidine. International<br />
Journal of Oncology 23:173-9, 2003.<br />
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and<br />
Lampidis, TJ. Multidrug resistance correlates<br />
with overexpression of Muc4 but inversely with<br />
P-glycoprotein and multidrug resistance related<br />
protein in transfected human melanoma cells.<br />
Biochemical Pharmacology 65:1419-25, 2003.<br />
RAKESH SINGAL, M.D.<br />
Associate Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Singal’s research focuses on the mechanisms<br />
that inactivate certain tumor-suppressor<br />
genes in prostate cancer. A common mode of<br />
such inactivation involves a modification (methylation)<br />
in DNA. By understanding how genes are<br />
silenced, treatments can be developed to activate<br />
them and thereby prevent the development and/<br />
or progression of prostate cancer. Researchers in<br />
Dr. Singal’s laboratory also are studying methylation<br />
of selected genes as a diagnostic and prognostic<br />
marker in prostate cancer.<br />
The present screening techniques for prostate<br />
cancer are very inefficient, and two out of three<br />
patients undergo prostate biopsy to detect cancer<br />
unnecessarily. <strong>Cancer</strong> patients often have a small<br />
amount of DNA circulating in their serum,<br />
thought to be released from the cancer cells.<br />
Dr. Singal’s laboratory has shown that certain<br />
methylated genes are present at a substantially<br />
higher percentage in prostate cancer tissue compared<br />
to benign prostatic conditions. Researchers<br />
are investigating if these methylated genes can<br />
be detected in serum DNA in patients with prostate<br />
cancer. If so, this test can be used as a part<br />
of prostate cancer screening, saving unnecessary<br />
prostate biopsies.<br />
DNA methylation plays a role during development<br />
by regulating gene expression. Another<br />
project in Dr. Singal’s laboratory focuses on understanding<br />
the role of methylation in regulating<br />
the expression of genes responsible for hemoglobin<br />
synthesis. Understanding the contribution of<br />
methylation to globin gene expression and the<br />
mechanisms involved will lead to the development<br />
of safe and effective therapies for globin<br />
gene disorders like thalassemia and sickle cell<br />
anemia.<br />
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SELECTED PUBLICATIONS<br />
2002<br />
Singal, R, vanWert, JM, and Ferdinand, L Jr.<br />
Methylation of alpha-type embryonic globin gene<br />
alpha pi represses transcription in primary erythroid<br />
cells. Blood 100:4217-22, 2002.<br />
Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and<br />
Ginder, GD. Methylation of promoter proximal<br />
transcribed sequences of an embryonic globin<br />
gene inhibits transcription in primary erythroid<br />
cells and promotes formation of a cell type-specific<br />
methyl cytosine binding complex. Journal of<br />
Biological Chemistry 277:1897-1905, 2002.<br />
Noss, KR, Singal, R, and Grimes, SR. Methylation<br />
state of the prostate specific membrane antigen<br />
(PSMA) CpG island in prostate cancer cell<br />
lines. Anticancer Research 22:1505-11, 2002.<br />
2003<br />
Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal,<br />
R, and Gill, S. Gynecomastia attributable to human<br />
chorionic gonadotropin-secreting giant cell<br />
carcinoma of lung. Endocrinology Practices<br />
9:233-35, 2003.<br />
JOYCE M. SLINGERLAND, M.D., PH.D.,<br />
F.P.R.C.(C)<br />
Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Slingerland’s research investigates how<br />
cancers escape negative growth controls. Following<br />
her discovery of a key inhibitor of cell<br />
cycle progression, p27, Dr. Slingerland and her<br />
colleagues went on to demonstrate that p27 levels<br />
are reduced in up to 60 percent of common human<br />
cancers (breast, prostate, lung, ovarian, and<br />
others), in association with poor patient prognosis.<br />
Dr. Slingerland showed that the therapeutic<br />
effect of antiestrogens in breast cancer requires<br />
the cyclin-dependent kinase (cdk) inhibitors p21<br />
and p27 to mediate growth arrest. Oncogenic<br />
activation of mitogenic signaling via the mitogenactivated<br />
protein kinase (MAPK) pathway deregulates<br />
p27 function, causing tamoxifen<br />
resistance in breast cancer. She provided key insights<br />
demonstrating the role of cell cycle inhibitors<br />
p15 and p27 as mediators of G1 arrest by<br />
transforming growth factor-beta (TGF-β) and<br />
demonstrated that cancer cells lose responsiveness<br />
to this growth inhibitory cytokine through loss or<br />
deregulation of p27. In a recent publication, her<br />
laboratory demonstrated that checkpoint loss<br />
during cancer progression makes p27 an essential<br />
mediator of arrest. They also showed that functional<br />
inactivation of p27 in human cancers can<br />
either occur through accelerated p27 degradation<br />
or through altered p27 phosphorylation leading<br />
to p27 mislocalization. The laboratory recently<br />
showed that activation of mitogenic signaling via<br />
the receptor tyrosine kinases and the phosphoinositol<br />
3’ kinase pathway alters p27 phosphorylation<br />
and function and the protein accumulates<br />
in the cytoplasm away from its targets in the<br />
nucleus. This work links oncogene activation<br />
with loss or inactivation of the cell cycle inhibitor,<br />
p27, elucidating a major mechanism of loss<br />
of growth control in cancer progression.<br />
Dr. Slingerland’s laboratory also is investigating<br />
the cause of aggressive estrogen receptor negative<br />
(ER-) breast cancers. Her group has found<br />
that oncogenic receptor tyrosine kinase and cSrc<br />
activation may not only activate mitogenic signaling<br />
leading to aggressive proliferation, but also<br />
lead to loss of detectable ER protein in ER negative<br />
(ER-) breast cancers. One third of newly diagnosed<br />
breast cancers are ER- and have a poor<br />
prognosis. Investigation of the mechanisms underlying<br />
the loss of ER expression showed that all<br />
of 70 primary ER- breast cancers expressed ER<br />
mRNA. Src or proteasome inhibition increased<br />
ER levels, and Src transfection stimulated both<br />
ligand activated ER transcriptional activity and<br />
ER proteolysis. Cotransfection of Her2 and Src<br />
reduced ER levels further. ER- primary breast<br />
cancers and cell lines showed increased Src activity<br />
compared to ER+ cancers and cell lines, and<br />
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the ER protein half-life was reduced in ERbreast<br />
cancer lines. These data support a model<br />
in which Her2 and cSrc cooperate with liganded<br />
ER to promote both ER dependent transcription<br />
and transcription linked ER proteolysis.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Donovan, JC, Rothenstein, JM, and Slingerland,<br />
JM. Non-malignant and tumor-derived cells differ<br />
in their requirement for p27Kip1 in transforming<br />
growth factor-beta-mediated G1 arrest.<br />
Journal of Biological Chemistry 277:41686-92,<br />
2002.<br />
Lian, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R,<br />
Connor, MK, Han, K, Lee, JH, Ciarallo, S,<br />
Catzavelos, C, Beniston R, Franssen, E, and<br />
Slingerland, JM . PKB/Akt phosphorylates p27,<br />
impairs nuclear import of p27 and opposes p27-<br />
mediated G1 arrest. Nature Medicine 8:1153-60,<br />
2002.<br />
Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH,<br />
Kotchetkov, R, Sandhu, C, Milic, A, and<br />
Slingerland, JM . Altered p27(Kip1) phosphorylation,<br />
localization, and function in human epithelial<br />
cells resistant to transforming growth<br />
factor beta-mediated G(1) arrest. Molecular and<br />
Cellular Biology 22:2993-3002, 2002.<br />
2003<br />
Connor, MK, Kotchetkov, R, Cariou, S, Resch,<br />
A, Lupetti, R, Beniston, RG, Melchior, F,<br />
Hengst, L, and Slingerland, JM . CRM1/Ranmediated<br />
nuclear export of p27(Kip1) involves a<br />
nuclear export signal and links p27 export and<br />
proteolysis. Molecular Biology of the Cell<br />
14:201-13, 2003.<br />
Liang, J and Slingerland, JM . Multiple Roles of<br />
the PI3K/PKB (Akt) Pathway in cell cycle progression.<br />
Cell Cycle 2:339-45, 2003.<br />
MARK S. SOLOWAY, M.D.<br />
Professor and Chairman of Urology<br />
DESCRIPTION OF RESEARCH<br />
Much of the work in the University of<br />
Miami’s department of Urology is devoted<br />
to better understanding the role of surgery in<br />
treating prostate, bladder, and kidney cancers.<br />
The department has established a rather unique<br />
database of more than 1,300 men who have had<br />
radical prostatectomy performed by one surgeon<br />
and their pathology has been read by one pathologist.<br />
Through the efforts of devoted researchers,<br />
they have reported on the relationship<br />
between a number of clinical and pathologic risk<br />
factors, e.g., positive surgical margin location,<br />
seminal vesicle invasion, and risk of relapse. This<br />
is critical when counseling patients regarding diagnosis,<br />
follow-up schedule and, most importantly,<br />
the need and type of additional treatment.<br />
Researchers in Dr. Soloway’s laboratory have<br />
introduced the concept of local anesthesia for<br />
prostate biopsies. This has the potential to benefit<br />
more than 500,000 men annually in the United<br />
States who undergo this otherwise rather painful<br />
procedure. More than 13 randomized studies<br />
confirm the researchers’ observation of the benefit<br />
of a periprostatic nerve block prior to ultrasound<br />
guided prostate biopsies.<br />
In an effort to minimize the morbidity of<br />
radical retropubic prostatectomy, Dr. Soloway has<br />
taken steps to enhance recovery without sacrificing<br />
cancer control. To this end, he has reported<br />
his results with nerve sparing, the omission of a<br />
pelvic drain, and the use of a cell saver to obviate<br />
the need for an allogeneic transfusion.<br />
In collaboration with Gaetano Ciancio,<br />
M.D., professor of Surgery and Urology, they<br />
have carefully detailed their surgical approach to<br />
large kidney tumors. They have adapted techniques<br />
developed for liver transplantation to reduce<br />
the morbidity and mortality related to<br />
surgery of large renal tumors, many of which involve<br />
extension into the vena cava.<br />
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Lastly, Dr. Soloway’s interest in bladder cancer<br />
continues. He has published the first article<br />
detailing the growth pattern of low-grade bladder<br />
tumors. Using a cohort of patients with lowgrade<br />
Ta tumors who were observed by periodic<br />
endoscopy, they were able to emphasize the safety<br />
of carefully monitoring such tumors to obviate<br />
the morbidity and cost of frequent outpatient<br />
surgery.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lokeshwar, VB and Soloway, MS. Re: Urine<br />
based markers of urological malignancy. Journal<br />
of Urology 167:1406-07, 2002.<br />
Lokeshwar, VB, Schroeder, GL, Selzer, MG,<br />
Hautmann, SH, Posey, JT, Duncan, RC, Watson,<br />
R, Rose, L, Markowitz, S, and Soloway, MS.<br />
Bladder tumor markers for monitoring recurrence<br />
and screening comparison of hyaluronic<br />
acid-hyaluronidase and BTA-Stat tests. <strong>Cancer</strong><br />
95:61-72, 2002.<br />
Lokeshwar, VB, Schroeder, GL, Carey, RI,<br />
Soloway, MS, and Iida, N. Regulation of hyaluronidase<br />
activity by alternative mRNA splicing.<br />
Journal of Biological Chemistry 277:33654-63,<br />
2002.<br />
2003<br />
Simon, MA, Lokeshwar, VB, and Soloway, MS.<br />
Current bladder cancer tests: unnecessary or beneficial?<br />
Critical Reviews in Oncology/Hematology<br />
47:91-107, 2003.<br />
Posey, JT, Soloway, MS, Ekici, S, Sofer, M,<br />
Civantos, F, Duncan, RC, and Lokeshwar, VB.<br />
Evaluation of the prognostic potential of hyaluronic<br />
acid and hyaluronidase (HYAL1) for prostate<br />
cancer. <strong>Cancer</strong> Research 63:2638-44, 2003.<br />
SHOU-CHING TANG, M.D., PH.D.<br />
Associate Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
BAG-1 is a recently identified anti-apoptotic<br />
protein that binds to Bcl-2, hepatocyte, and<br />
platelet-derived growth factor receptors, enhancing<br />
their inhibition of apoptosis. It also binds to<br />
heat shock proteins, RAF-1 serine/threonine kinase,<br />
and hormone receptors and modulates their<br />
functions. Researchers in Dr. Tang’s laboratory<br />
detected the presence of one new BAG-1 isoform,<br />
p29. They showed that the four BAG-1 isoforms<br />
are localized differentially in subcellular compartments<br />
and in various tissues, suggesting that they<br />
perform different functions. They recently demonstrated<br />
that each BAG-1 isoform has a differing<br />
ability to inhibit apoptosis induced by various<br />
apoptosis-inducing agents. On the other hand,<br />
antisense against BAG-1 sensitized cells to<br />
apoptosis was induced by various chemotherapeutic<br />
agents. More significantly, these researchers<br />
observed the overexpression of BAG-1 in the<br />
majority of breast and lung cancer patients and<br />
its prognostic value. In addition, they observed<br />
the coexpression of BAG-1 with Bcl-2, p53, and<br />
estrogen receptor/progesterone receptor (ER/PR)<br />
in breast cancer tissues. They have isolated the<br />
BAG-1 promoter region and noted its up-regulation<br />
by the mutant p53. The laboratory also has<br />
raised monoclonal antibodies against individual<br />
BAG-1 isoforms, allowing for clinical correlation<br />
of BAG-1 expression and disease course. Current<br />
research at the basic molecular biology level involves<br />
the study of BAG-1 expression control and<br />
its interaction with other cellular proteins, including<br />
Bcl-2, ER/PR, and hsp to explore how<br />
BAG-1 inhibits apoptosis. At the clinical research<br />
level, research involves the development of BAG-<br />
1 Mab and antisense in the prognosis and prediction<br />
to treatment response in a variety of solid<br />
tumors.<br />
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SELECTED PUBLICATIONS<br />
2002<br />
Ding, Z, Tang, S-C, Weerasinghe, P, Yang, X,<br />
Pater, A, and Liepins, A. The alkaloid sanguinarine<br />
is effective against multi-drug resistance in<br />
human cervical cells via bimodal cell death. Biochemical<br />
Pharmacology 63:1415-21, 2002.<br />
Ding, Z, Green, AG, Yang, X, Chernenko, G,<br />
Tang, S-C, and Pater, A. Retinoic acid inhibits<br />
telomerase activity and downregulates expression<br />
but does not affect splicing of hTERT: correlation<br />
with cell growth rate inhibition in an in vitro<br />
cervical carcinogenesis/multidrug-resistance<br />
model. Experimental Cell Research 272:185-91,<br />
2002.<br />
Ding, Z, Tang, S-C, Weerasinghe, P, Yang, X,<br />
Chernenko, G, Pater, A, and Liepins, A. The alkaloid<br />
sanguirine is effective against multidrug<br />
resistance in human cervical cells via bimodal cell<br />
death. Biochemical Pharmacology 63:1415-21,<br />
2002.<br />
Tang, S-C. BAG-1, an anti-apoptotic tumor<br />
marker. (Invited Review) IUBMB Life 53:99-<br />
105, 2002.<br />
Chen, J, Chernenko, G, Xiong, J and Tang, S-C.<br />
Distinct BAG-1 isoforms have different antiapoptotic<br />
functions in BAG-1-transfected C33A<br />
human cervical carcinoma cell line. Oncogene<br />
21:7050-59, 2002.<br />
2003<br />
Tang, S-C. Differential anti-apoptotic function<br />
of BAG-1 isoforms in human malignancy. Recent<br />
Research and Development in Biophysics and<br />
Biochemistry 3:427-44, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Cloned mouse and human BAG-1 genes and its<br />
promoter.<br />
• Discovered the mechanism by which four BAG-<br />
1 isoforms are generated.<br />
• Discovered the possible prognostic value of<br />
BAG-1 in breast and lung cancer.<br />
• Generated BAG-1-isoform-specific Mab’s<br />
(patent pending).<br />
• Generated BAG-1 antisense cDNA and siRNA.<br />
• Discovered BAG-1’s involvement in chemotherapy<br />
resistance.<br />
• Developed Eastern Cooperative Oncology<br />
Group (ECOG) protocol using BAG-1 as predictive<br />
marker in the treatment of NSCLC.<br />
KHALED A. TOLBA, M.D.<br />
Assistant Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
During the past five years, Dr. Tolba has been<br />
developing immunotherapeutic strategies for<br />
B-cell hematologic malignancies, with particular<br />
interest in chronic lymphocytic leukemia (CLL).<br />
CLL is the most common leukemia in the Western<br />
hemisphere. As a relatively slow-progressing<br />
tumor with readily accessible tumor cells, it offers<br />
an opportunity to develop and test immunotherapeutic<br />
interventions. A number of profound<br />
immunologic deficiencies affecting both the B<br />
and T-cell responses, however, have posed a challenge<br />
to immune therapy of CLL.<br />
The laboratory has co-developed and<br />
adapted the use of herpes simplex virus (HSV)<br />
amplicons for gene transduction of CLL cells.<br />
Using CD40L as an effector molecule, they have<br />
shown robust induction of co-stimulatory molecules<br />
on transduced and bystander cells and in<br />
roughly one-third of tested patients demonstrated<br />
the capacity to generate cytotoxic T lymphocytes<br />
(CTL) activity. This capacity to elicit autologous<br />
CTL response, however, was not universal as<br />
more than half the patients tested failed to mount<br />
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such a response despite adequate up-regulation<br />
of costimulatory signal on both transduced and<br />
bystander CLL cells. In addition to being a<br />
highly efficient gene transfer vector, herpes simplex<br />
virus (HSV)-based amplicons possess the<br />
capacity to engage and activate different elements<br />
of the innate immune system. Currently, the<br />
laboratory is studying various aspects of HSV<br />
amplicon/innate immune interaction and how<br />
this might influence the outcome of an adaptive<br />
anti-tumor immune response.<br />
Immune therapeutic strategies targeting the<br />
innate immune system might offer an alternative<br />
pathway to bypass inherent CD8 + T-cell defects,<br />
and effectively mount a systemic anti-tumor immune<br />
response. Dr. Tolba and his colleagues are<br />
currently exploring how HSV amplicon interacts<br />
with the family of toll-like (TL) receptors and<br />
up-regulates NKG2D ligands on target cells.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,<br />
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD.<br />
Herpes simplex virus (HSV)-amplicon-mediated<br />
delivery of LIGHT enhances the antigen-presenting<br />
capacity of chronic lymphocytic leukemia.<br />
Molecular Therapy 6:455-63, 2002.<br />
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,<br />
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,<br />
JD. Herpes simplex virus (HSV) amplicon-mediated<br />
codelivery of secondary lymphoid tissue<br />
chemokine and CD40L results in augmented antitumor<br />
activity. <strong>Cancer</strong> Research 62:6545-51,<br />
2002.<br />
Rosenblatt, JD, Shin, SU, Nechustan, H, Yi,<br />
KH, and Tolba, KA. Potential role of<br />
chemokines in immune therapy of cancer. Israel<br />
Medical Association Journal 4:1054-59, 2002.<br />
VLADIMIR VINCEK, M.D., PH.D.<br />
Associate Professor of Pathology<br />
DESCRIPTION OF RESEARCH<br />
Progress in the understanding of molecular<br />
events involved in the development and progression<br />
of human disease is revolutionizing the<br />
way diseases are diagnosed and treated. Physicians<br />
and scientists now are harnessing the power of<br />
molecular techniques to diagnose and prognosticate<br />
pathologic disorders. Furthermore, it is now<br />
possible to direct therapeutic agents to specific<br />
products expressed by diseased cells without affecting<br />
normal tissues. On the other hand, while<br />
standard histopathologic methods maintain tissue<br />
architecture for morphologic assessment, they do<br />
not preserve macromolecules. The extraction of<br />
nucleic acids from formaldehyde-fixed, paraffinembedded<br />
tissue, the most widely available material<br />
for clinical studies, is a notoriously unreliable<br />
and irreproducible process. Therefore, macromolecules<br />
usually are extracted from fresh or snapfrozen<br />
tissue specimens. Fresh or frozen tissue<br />
specimens, however, are of limited value for the<br />
assessment of histomorphology and cannot be<br />
utilized for long-term retrospective studies. Similarly,<br />
currently available tissue preservatives that<br />
protect nucleic acids cause considerable damage<br />
to the cell and tissue architecture and render<br />
them unsuitable for histomorphologic evaluation.<br />
Current studies in this laboratory show that<br />
it is feasible to simultaneously protect histomorphology<br />
and the integrity of macromolecules in<br />
fixed and processed tissue. The UMFIX reagent,<br />
developed in collaboration with other members<br />
of the Department of Pathology, seems to provide<br />
enormous advantage over the conventional fixation<br />
methods in allowing diagnosis, prognostication,<br />
and identification of treatment targets in<br />
patient samples.<br />
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SELECTED PUBLICATIONS<br />
2002<br />
Malek, TR, Yu, A, Vincek, V, Scibelli, P, and<br />
Kong, L. CD4 regulatory T cells prevent lethal<br />
autoimmunity in IL-2Rbeta-deficient mice. Implications<br />
for the nonredundant function of IL-2.<br />
Immunity 17:167-78, 2002.<br />
Morales, A, Essenfeld, H, Dubane, C, Vincek, V,<br />
and Nadji, M. Continuous-specimen-flow, highthroughput,<br />
1-hour tissue processing. Archives of<br />
Pathology & Laboratory Medicine 126:584-90,<br />
2002.<br />
2003<br />
Vincek, V, Knowles, J, and Nassiri, M. p63<br />
mRNA expression in normal human tissue. Anticancer<br />
Research 23:3945-48, 2003.<br />
Vincek, V, Nassiri, M, Knowles, J, Nadji, M, and<br />
Morales, AR. Preservation of tissue RNA in normal<br />
saline. Laboratory Investigation 83:137-38,<br />
2003.<br />
Jacob, SE, Nassiri, M, Kerdel, FA, and Vincek, V.<br />
Rapid measurement of multiple cytokines in psoriasis<br />
patients and correlation with disease severity.<br />
Mediators of Inflammation 12:309-13, 2003.<br />
Adkins, B, Bu, Y, Vincek, V, and Guevara, P.<br />
The primary responses of murine neonatal lymph<br />
node CD4 + cells are Th2-skewed and are sufficient<br />
for the development of Th2-biased memory.<br />
Clinical & Developmental Immunology 10:43-<br />
51, 2003.<br />
Vincek, V, Nassiri, M, Nadji, M., and Morales,<br />
AR. A novel tissue preservative that protects macromolecules<br />
(DNA, RNA, protein) and<br />
histomorphology in clinical samples. Laboratory<br />
Investigation 83:1-9, 2003.<br />
Jacob, SE, Berman, B, Nassiri, M, and Vincek, V.<br />
Topical application of imiquimod 5% cream to<br />
keloids alters expression genes associated with<br />
apoptosis. British Journal of Dermatology 149:1-<br />
4, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Patent pending for alcohol-based UMFIX preservative<br />
that preserves histomorphology and<br />
macromolecules.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
T U M O R C E L L B I O L O G Y P R O G R A M<br />
PROGRAM LEADER<br />
Kermit L. Carraway, Ph.D.<br />
Professor of Cell Biology and Anatomy<br />
DESCRIPTION OF PROGRAM<br />
The Tumor Cell Biology Program currently<br />
comprises 28 faculty members in 11 different<br />
departments at the University of Miami<br />
School of Medicine. Faculty members are chosen<br />
based on the potential of their research to contribute<br />
to important aspects in the understanding<br />
of cancer cell biology. Faculty members must have<br />
peer-reviewed cancer related research funding in<br />
a field aligned with the scientific goals of the program<br />
or be newly recruited faculty investigators.<br />
GOALS OF PROGRAM<br />
The overall goal of the Tumor Cell Biology Program<br />
is to develop knowledge in the area of cell<br />
biology that can be applied to translational research<br />
on neoplastic disease. The focus of the individual<br />
studies varies widely, from gene therapy<br />
to the ultrastructural analyses of protein; however,<br />
all investigators are involved in cutting-edge<br />
research using the developing methods of molecular<br />
biology and cell structural analysis to ask<br />
questions important to tumor cell biology.<br />
The specific aims of the program are to:<br />
1) Understand how genetic information is maintained,<br />
transferred, and translated into functional<br />
cell proteins, a fundamental issue<br />
throughout the history of cancer research.<br />
2) Determine how tumor cells interact with other<br />
cells and their environment, particularly the<br />
molecular species and associations that favor or<br />
disfavor those interactions. This issue is critically<br />
important for understanding metastasis<br />
of tumors, the process that usually determines<br />
mortality of cancer patients.<br />
3) Determine how signaling pathways and<br />
molecules transmit and integrate information,<br />
which determines cell fate, including cell structure<br />
and function. Included in such analyses are<br />
the mechanisms by which the molecular components<br />
of signaling and metabolic pathways<br />
are localized in cells to perform their particular<br />
roles.<br />
All of these questions and approaches are important<br />
to understanding how tumor cells behave<br />
and determining whether specific tumor cell<br />
behaviors can be exploited in combating cancer.<br />
Developing such translational applications is the<br />
ultimate goal of the Tumor Cell Biology<br />
Program.<br />
PARTICIPANTS<br />
Burnstein, Kerry L., Ph.D.<br />
Molecular and Cellular Pharmacology<br />
Carraway, Kermit L., Ph.D.<br />
Cell Biology and Anatomy<br />
Deutscher, Murray P., Ph.D.<br />
Biochemistry and Molecular Biology<br />
D’Urso, Gennaro, Ph.D.<br />
Molecular and Cellular Pharmacology<br />
Fletcher, Terace M., Ph.D.<br />
Biochemistry and Molecular Biology<br />
Franzmann, Elizabeth J., M.D.<br />
Otolaryngology<br />
Han, Zhiyong, Ph.D.<br />
Biology<br />
Harris, Thomas K., Ph.D.<br />
Biochemistry and Molecular Biology<br />
King, Mary Lou, Ph.D.<br />
Cell Biology and Anatomy<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
Lampidis, Theodore J., Ph.D.<br />
Cell Biology and Anatomy<br />
Li, Jie, M.D., Ph.D.<br />
Dermatology and Cutaneous Surgery<br />
Liu, Chia-Yang, Ph.D.<br />
Ophthalmology<br />
Lokeshwar, Balakrishna L., Ph.D.<br />
Urology<br />
Lokeshwar, Vinata B., Ph.D.<br />
Urology<br />
Malhotra, Arun, Ph.D.<br />
Biochemistry and Molecular Biology<br />
Mayeda, Akila, Ph.D.<br />
Biochemistry and Molecular Biology<br />
Moraes, Carlos T., Ph.D.<br />
Neurology<br />
Perez, Aymee, Ph.D.<br />
Cell Biology and Anatomy<br />
Salas, Pedro J. I., M.D., Ph.D.<br />
Cell Biology and Anatomy<br />
Shonukan, Oluwatoyin, M.D.<br />
Medicine<br />
Singal, Rakesh, M.D.<br />
Medicine<br />
Slingerland, Joyce M., M.D., Ph.D., F.P.R.C. (C)<br />
Medicine<br />
Verde, Fulvia, Ph.D.<br />
Molecular and Cellular Pharmacology<br />
Weed, Donald T., M.D., F.A.C.S.<br />
Otolaryngology<br />
Welsh, Catherine F., M.D.<br />
Medicine<br />
Werner, Rudolf K., Ph.D.<br />
Biochemistry and Molecular Biology<br />
Wyche, James, Ph.D.<br />
Biology<br />
Zimmers, Teresa A., Ph.D.<br />
Surgery<br />
HIGHLIGHTS/DISCOVERIES<br />
• MUC4 expression potentiates the phosphorylation/activation<br />
of the ErbB2 and ErbB3 tyrosine<br />
kinase receptors induced by neuregulin,<br />
providing a mechanism by which MUC4 may<br />
contribute to tumor progression through<br />
changes in cell signaling pathways (K. Carraway).<br />
• MUC4 in mammary gland is regulated at the<br />
post-transcriptional level by extracellular matrix<br />
(basement membrane) and by transforming<br />
growth factor-beta. Responses to both of these<br />
are known to change during breast cancer progression<br />
(K. Carraway).<br />
• MUC4 overexpression increases primary tumor<br />
growth in nude mice, acting as an antiapoptotic<br />
agent in the growing tumors and in<br />
cell culture (K. Carraway).<br />
• MUC4 regulates the localization of the receptor<br />
tyrosine kinase ErbB2 in polarized epithelial<br />
cells (K. Carraway).<br />
• Vitamin D inhibits the cell cycle by promoting<br />
nuclear exclusion of cyclin dependent kinase 2,<br />
opening new avenues for prostate cancer<br />
therapy. Regulation of cdk2 localization represents<br />
a new regulatory paradigm in G1 to S-<br />
phase progression (K. Burnstein).<br />
• Pol ε is required for initiation of DNA replication,<br />
suggesting that it provides multiple functions<br />
in promoting DNA replication, one of<br />
which is to facilitate assembly of the DNA replication<br />
initiation complex (G. D’Urso).<br />
• Discovery of a new endoribonuclease, RNase G<br />
(M. Deutscher).<br />
• Oligoribonuclease is an essential component of<br />
mRNA degradation (M. Deutscher).<br />
• Development of an efficient, cell-free translation<br />
system for mammalian cells (M.<br />
Deutscher).<br />
• Discovery of CD44v3-containing isoforms in<br />
head and neck squamous cell tumor tissues and<br />
cell lines (E. Franzmann).<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
• Development of a novel thermodynamically<br />
balanced inside-out method of polymerase<br />
chain reaction (PCR)-based synthesis to generate<br />
codon-optimized human kinase genes<br />
(T. Harris).<br />
• VegT, a T-box transcription factor, is essential<br />
for three important steps in development (M.<br />
L. King).<br />
• Glycolytic inhibitors can be used to specifically<br />
target the hypoxic slow-growing cells of solid<br />
tumors and thereby increase the efficacy of current<br />
chemotherapeutic and irradiation protocols<br />
designed to kill rapidly dividing cells (T.<br />
Lampidis).<br />
• In osteosarcoma, the addition of the glycolytic<br />
inhibitor 2-Deoxyglucose (2-DG) increases the<br />
efficacy of Adriamycin in reducing tumor size<br />
and prolonging survival (T. Lampidis).<br />
• In non-small cell lung cancer, the addition of 2-<br />
DG increases the effectiveness of taxol (T.<br />
Lampidis).<br />
• Microvascular endothelial cells produce two<br />
extracellular matrix proteins, laminin-8 and<br />
laminin-10, which play important roles in tumor<br />
angiogenesis (J. Li).<br />
• Discovery of an imbalance between the levels of<br />
matrix metalloproteinases (MMPs) (overproduction)<br />
and their natural inhibitors (underproduction)<br />
in invasive prostate cancer cells (B.<br />
Lokeshwar).<br />
• Identification of a novel chemically modified<br />
non-antimicrobial tetracycline (COL-3) as an<br />
effective anti-metastatic drug with the potential<br />
to treat prostate cancer metastatic to bone;<br />
completion of NCI phase I trial of this drug (B.<br />
Lokeshwar).<br />
• Development of the HA-HAase urine test, a<br />
non-invasive test that is about 90 percent accurate<br />
in detecting bladder cancer and monitoring<br />
its recurrence (V. Lokeshwar).<br />
• Development of HA and HAase tests that are<br />
greater than 85 percent accurate prognostic<br />
indicators for prostate cancer (V. Lokeshwar).<br />
• Demonstration of the function of tumor-derived<br />
HAase in bladder tumor growth and<br />
muscle invasion (V. Lokeshwar).<br />
• Splicing activator RNPS1 is incorporated in the<br />
early splicing complex, stimulating formation of<br />
the ATP-dependent splicing complex, and subsequently<br />
increasing generation of both intermediate<br />
and final spliced products (A. Mayeda).<br />
• Cells with defective mitochondrial respiration<br />
can be more resistant to cell death, which might<br />
explain the presence of mtDNA mutations in<br />
some cancers (C. Moraes).<br />
• Mitochondrial defects stimulate the production<br />
of metalloproteases, which in turn promotes<br />
tissue invasion (C. Moraes).<br />
• Up-regulation of ErbB2 ligand Muc4 expression<br />
correlates with the overexpression of transcription<br />
factor PEA3 and the receptor tyrosine<br />
kinase ErbB2 (A. Perez).<br />
• Observation of the attachment of centrosomes<br />
to intermediate filaments (P. Salas).<br />
• Nerve growth factor (NGF) mediates the invasiveness<br />
of melanoma cells in vitro by inducing<br />
the coupling of the intracellular domain of the<br />
p75 neurotrophin receptor with the actin cytoskeleton<br />
(O. Shonukan).<br />
• Neurotrophin-induced melanoma invasiveness<br />
is mediated by signals generated through PI-3<br />
kinase (O. Shonukan).<br />
• NGF induces the disruption of cadherin-mediated<br />
cell-cell adhesion, thereby permitting melanoma<br />
cells to dissociate from the keratinocytes<br />
in the epidermis, and invade the dermis, from<br />
whence they metastasize to distant sites (O.<br />
Shonukan).<br />
• Aberrant p27 in breast cancer cells causes them<br />
to be unable to respond to antiestrogen therapies<br />
such as Tamoxifen (J. Slingerland).<br />
• Activation of the Src pathway is linked with<br />
both the lack of detectable estrogen receptor<br />
(ER) and clinically aggressive behavior of breast<br />
cancers (J. Slingerland).<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
• Discovery of estrogen regulation of the gap<br />
junction protein connexin 43 via an internal<br />
ribosome entry site for translation (R. Werner).<br />
• Discovery of the requirement for Rho family<br />
GTPases for key adhesion-dependent G1<br />
events, including cyclin D1 expression, Rb<br />
phosphorylation, and cyclin A expression (C.<br />
Welsh).<br />
KERRY L. BURNSTEIN, PH.D.<br />
Professor of Molecular and Cellular<br />
Pharmacology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Burnstein’s research focuses on signaling<br />
mechanisms that govern prostate cancer cell<br />
cycle and androgen responsiveness. Vitamin D is<br />
of particular interest, stemming from epidemiological<br />
data showing a relationship between vitamin<br />
D deficiency and increased risk of prostate<br />
cancer mortality. It has been shown that vitamin<br />
D inhibits the growth of prostate cancer cell lines<br />
and primary cell cultures derived from human<br />
prostate tumors. Researchers in Dr. Burnstein’s<br />
laboratory found that the mechanism underlying<br />
such growth arrest is a vitamin D-induced cellular<br />
accumulation in the initial phase of the cell<br />
cycle, G1. They demonstrated that vitamin D-<br />
mediated antiproliferative effects are not dependent<br />
on androgen/AR. This finding is of clinical<br />
relevance, as a requirement for androgen would<br />
severely limit use of vitamin D in advanced prostate<br />
cancer, which is customarily treated by androgen<br />
ablation. Furthermore, Dr. Burnstein’s<br />
laboratory showed that vitamin D causes upregulation<br />
of specific and potent cell cycle inhibitors,<br />
p21 and p27, a finding that has potentially<br />
important therapeutic implications. Her laboratory<br />
recently made the novel discovery that vitamin<br />
D mediates the nuclear exclusion of cyclin<br />
dependent kinase (cdk)-2, thereby decreasing its<br />
activity and promoting p27 stability. Current efforts<br />
are directed at understanding vitamin D<br />
regulation of cdk-2 nucleocytoplasmic trafficking.<br />
A finding that emerged from the studies on<br />
vitamin D was that the most highly malignant<br />
prostate cancer cell lines expressed very low levels<br />
of cdk inhibitors. Subsequent studies on human<br />
prostate cancer biopsies confirmed this observation.<br />
Because of these findings and the fact that<br />
the genes encoding these inhibitors are rarely mutated,<br />
Dr. Burnstein decided to investigate possible<br />
intracellular signaling alterations that might<br />
suppress levels of these inhibitory proteins and<br />
contribute to uncontrolled cell proliferation. In<br />
collaboration with Catherine F. Welsh, M.D., she<br />
made the novel observation that Rac1, a Ras-related<br />
Rho GTPase (small G protein), exhibits<br />
high activity in the more malignant prostate<br />
cancer cells. Specific inhibition of Rac1 in these<br />
cells results in increased levels of the cdk inhibitor<br />
p21 and decreased proliferation. These findings<br />
are unique in describing a role for Rac1 in the<br />
regulation of p21 and implicate the Rac1 signaling<br />
pathway as a therapeutic target. Recently, researchers<br />
found that a protein that activates Rac1<br />
also enhances the transcriptional activity<br />
of the androgen receptor (AR). This observation<br />
provides a tantalizing link between two critical<br />
signaling pathways in prostate cancer and suggests<br />
a plausible mechanism for AR activity<br />
during progression to androgen independence.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Yang, ES, Maiorino, CA, Roos, BA, Knight, SR,<br />
and Burnstein, KL . Vitamin D-mediated growth<br />
inhibition of an androgen-ablated LNCaP cell<br />
line model of human prostate cancer. Molecular<br />
and Cellular Endocrinology 186:69-79, 2002.<br />
Whitlatch, LW, Young, MV, Schwartz, GG,<br />
Flanagan, JN, Burnstein, KL , Lokeshwar, BL,<br />
Rich, ES, Holick, MF, and Chen, TC. 25-<br />
Hydroxyvitamin D-1alpha-hydroxylase activity is<br />
diminished in human prostate cancer cells and is<br />
enhanced by gene transfer. Journal of Steroid Biochemistry<br />
and Molecular Biology 81:135-40, 2002.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
2003<br />
Kizu, R, Okamura, K, Toriba, A, Kakishima, H,<br />
Mizokami, A, Burnstein, KL , and Hayakawa, K.<br />
A role of aryl hydrocarbon receptor in the<br />
antiandrogenic effects of polycyclic aromatic hydrocarbons<br />
in LNCaP human prostate carcinoma<br />
cells. Archives of Toxicology 77:335-43, 2003.<br />
Yang, E and Burnstein, KL . Vitamin D inhibits<br />
G1 to S progression in LNCaP prostate cancer<br />
cells through p27Kip1 stabilization and Cdk2<br />
mislocalization to the cytoplasm. Journal of Biological<br />
Chemistry 278:46862-68, 2003.<br />
Chen, TC, Holick, MF, Lokeshwar, BL,<br />
Burnstein, KL , and Schwartz, GG. Evaluation of<br />
vitamin D analogs as therapeutic agents for prostate<br />
cancer. Recent Results in <strong>Cancer</strong> Research<br />
164:273-88, 2003.<br />
Kizu, R, Okamura, K, Toriba, A, Mizokami, A,<br />
Burnstein, KL , Klinge, CM, and Hayakawa, K.<br />
Antiandrogenic activities of diesel exhaust particle<br />
extracts in PC3/AR human prostate carcinoma<br />
cells. Toxicology Sciences 76:299-309, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Vitamin D inhibits the cell cycle by promoting<br />
nuclear exclusion of cdk-2, which opens up new<br />
avenues for prostate cancer therapy. Further,<br />
regulation of cdk-2 localization represents a<br />
new regulatory paradigm in G1 to S phase<br />
progression.<br />
KERMIT L. CARRAWAY, PH.D.<br />
Professor of Cell Biology and Anatomy<br />
DESCRIPTION OF RESEARCH<br />
For much of the past decade, Dr. Carraway’s<br />
primary research effort has been to examine<br />
the role of cell surface glycoproteins in mammary<br />
cancer, focusing on a particular glycoprotein<br />
complex (sialomucin complex, MUC4, rat<br />
Muc4) that his laboratory discovered about 20<br />
years ago. This complex has both mucin- and<br />
growth factor-containing subunits. This putative<br />
bi-functionality can potentially contribute to two<br />
of the major attributes of cancer cells, loss of adhesiveness,<br />
and autonomous growth. Consistent<br />
with both of those activities, MUC4 has been<br />
implicated in tumor metastasis. The anti-adhesive<br />
function of MUC4 allows it to block tumor cell<br />
killing by lymphokine-activated killer (LAK)<br />
cells, a mechanism that permits the MUC4-overexpressing<br />
tumor cells to escape immune surveillance.<br />
One of the two growth factor domains of<br />
the transmembrane subunit of MUC4 has been<br />
shown to act as an intramembrane ligand for the<br />
class I tyrosine kinase growth factor receptor<br />
ErbB2/HER2/Neu. Binding of MUC4 as a<br />
ligand to ErbB2 potentiates tyrosine phosphorylation<br />
of the receptor and its co-receptor ErbB3,<br />
when the latter is stimulated with its soluble<br />
ligand Neuregulin.<br />
Researchers in Dr. Carraway’s laboratory are<br />
currently investigating the effects of this receptor<br />
modulation on downstream signaling pathways<br />
and cellular functions. Recently, they have found<br />
that induction of MUC4 overexpression in a<br />
melanoma tumor cell model potentiates both primary<br />
tumor growth and metastasis when the tumors<br />
are injected into nude mice. The former is<br />
correlated with a reduction in apoptosis in the<br />
MUC4-overexpressing animals. One important<br />
question is whether the anti-apoptotic effects of<br />
MUC4 result from its growth factor domains or<br />
other features of its structure. Recent results have<br />
shown that MUC4 can regulate both the phosphorylation<br />
and location of ErbB2 in polarized<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
epithelial cells, providing two mechanisms by<br />
which it can regulate signaling. Since MUC4 has<br />
been implicated in breast cancer progression, it is<br />
of interest to know how it is regulated in the<br />
mammary gland. Investigations of primary mammary<br />
epithelial cells indicate a major role for<br />
post-transcriptional regulation. Interactions with<br />
the extracellular matrix regulate MUC4 expression<br />
at the translational level, while transforming<br />
growth factor-beta (TGF-β) regulates it at the<br />
post-translational level. Both of these types of<br />
regulation are lost in rat mammary tumor cells,<br />
and both are known to change during human<br />
breast cancer progression. These and other results<br />
suggest that MUC4 acts as a “tumor progressor”<br />
gene rather than a primary oncogene. Thus,<br />
MUC4 might serve as a future target for prognosis<br />
and therapies in breast cancer.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Carraway, KL , Perez, A, Idris, N, Jepson, S,<br />
Arango, M, Komatsu, M, Haq, B, Price-Schiavi,<br />
SA, Zhang, J, and Carraway, CA. Muc4/<br />
sialomucin complex, the intramembrane ErbB2<br />
ligand, in cancer and epithelia: to protect and to<br />
survive. Progress in Nucleic Acid Research in Molecular<br />
Biology 71:149-85, 2002.<br />
Swan, JS, Arango, ME, Carothers Carraway, CA,<br />
and Carraway, KL . An ErbB2-Muc4 complex in<br />
rat ocular surface epithelia. Current Eye Research<br />
24:397-402, 2002.<br />
Jepson, S, Komatsu, M, Haq, B, Arango, ME,<br />
Huang, D, Carraway, CA, and Carraway, KL .<br />
Muc4/sialomucin complex, the intramembrane<br />
ErbB2 ligand, induces specific phosphorylation<br />
of ErbB2 and enhances expression of p27 (kip),<br />
but does not activate mitogen-activated kinase or<br />
protein kinase B/Akt pathways. Oncogene<br />
21:7524-32, 2002.<br />
Komatsu, M, Arango, ME, and Carraway, KL .<br />
Synthesis and secretion of Muc4/sialomucin<br />
complex: implication of intracellular proteolysis.<br />
Biochemical Journal 368:41-48, 2002.<br />
2003<br />
Ramsauer, VP, Carothers Carraway, CA, Salas, PJ,<br />
and Carraway, KL . Muc4/Sialomucin complex,<br />
the intramembrane ErbB2 ligand, translocates<br />
ErbB2 to the apical surface in polarized Epithelial<br />
cells. Journal of Biological Chemistry 278:30142-<br />
47, 2003.<br />
Carraway, KL , Ramsauer, VP, Haq, B, and<br />
Carothers Carraway, CA. Cell signaling through<br />
membrane mucins. BioEssays 25:66-71, 2003.<br />
Fischer, BM, Cuellar, JG, Diehl, ML, deFreytas,<br />
AM, Zhang, J, Carraway, KL , and Voynow, JA.<br />
Neutrophil elastase increases MUC4 expression<br />
in normal human bronchial epithelial cells.<br />
American Journal of Physiology. Lung Cellular<br />
and Molecular Physiology 284:L671-79, 2003.<br />
Hu, YP, Haq, B, Carraway, KL , Savaraj, N, and<br />
Lampidis, TJ. Multidrug resistance correlates<br />
with overexpression of Muc4 but inversely with<br />
P-glycoprotein and multidrug resistance related<br />
protein in transfected human melanoma cells.<br />
Biochemical Pharmacology 65:1419-25, 2003.<br />
Soto, P, Price-Schiavi, SA, and Carraway, KL .<br />
SMAD2 and SMAD7 involvement in the posttranslational<br />
regulation of Muc4 via the transforming<br />
growth factor-beta and interferon-gamma<br />
pathways in rat mammary epithelial cells. Journal<br />
of Biological Chemistry 278:20338-44, 2003.<br />
Perez, A, Barco, R, Fernandez, I, Price-Schiavi,<br />
SA, and Carraway, KL . PEA3 transactivates the<br />
Muc4/sialomucin complex promoter in mammary<br />
epithelial and tumor cells. Journal of Biological<br />
Chemistry 278(38):36942-52, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• MUC4 expression potentiates the phosphorylation/activation<br />
of the ErbB2 and ErbB3 tyrosine<br />
kinase receptors induced by neuregulin,<br />
providing a mechanism by which MUC4 may<br />
contribute to tumor progression through<br />
changes in cell signaling pathways.<br />
70<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
• MUC4 in the mammary gland is regulated at<br />
the post-transcriptional level by extracellular<br />
matrix (basement membrane) and by TGF-β.<br />
Responses to both of these are known to change<br />
during breast cancer progression.<br />
• MUC4 regulation in the uterus during pregnancy<br />
is at the transcript level, indicating the<br />
complexity of the control of its gene.<br />
• MUC4 overexpression increases primary tumor<br />
growth in nude mice, acting as an antiapoptotic<br />
agent in the growing tumors and in<br />
cell culture.<br />
• MUC4 regulates the localization of the receptor<br />
tyrosine kinase ErbB2 in polarized epithelial<br />
cells.<br />
MURRAY P. DEUTSCHER, PH.D.<br />
Professor and Chairman of Biochemistry<br />
and Molecular Biology<br />
DESCRIPTION OF RESEARCH<br />
Researchers in Dr. Deutscher’s laboratory<br />
focus on two major areas of research. One<br />
deals with the identification, characterization,<br />
and determination of the physiological role of<br />
RNA processing and degradative enzymes. To<br />
date, eight exoribonucleases and seven endo-ribonucleases<br />
have been identified in Escheichia coli.<br />
Many of the enzymes have been purified and<br />
studied for their catalytic properties. Mutations<br />
have been constructed in the genes for each of<br />
these enzymes, and the genes have been cloned<br />
and their sequences identified. Several of these<br />
enzymes have now been shown to participate in<br />
transfer RNA and ribosomal RNA maturation,<br />
and in messenger RNA degradation. The availability<br />
of the purified enzymes and of mutants<br />
lacking these RNases is being used to elucidate<br />
complete RNA maturation pathways and to<br />
study the regulation of these processes. In addition,<br />
his studies have shown that cells contain<br />
RNA quality control mechanisms for eliminating<br />
defective RNA molecules.<br />
The second area of investigation deals with<br />
the translation system of mammalian cells. Protein<br />
synthesis in mammalian cells proceeds as<br />
much as 100-fold faster than synthesis in isolated<br />
cell-free systems. What is lost in these in vitro<br />
systems is the organization that normally exists in<br />
vivo. They have shown that many of the components<br />
of the translation apparatus are associated<br />
with each other, and that protein synthesis is a<br />
“channeled” pathway, i.e., the aminoacyl-tRNA<br />
and peptidyl-tRNA intermediates are directly<br />
transferred from one component of the translation<br />
apparatus to the next without dissociation<br />
into the cellular fluid. A permeabilized mammalian<br />
cell system has been developed that allows<br />
study of these events in close to an in vivo situation.<br />
Studies are in progress to determine the role<br />
of the actin cytoskeleton in maintaining the organization<br />
of the translation system and to identify<br />
other factors associated with the translation apparatus<br />
that affect its function. Dr. Deutscher’s<br />
laboratory has taken this work further to show<br />
that the whole mammalian cell is highly organized<br />
and that macromolecules don’t diffuse, but move<br />
in motor-driven processes on the cytoskeleton.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Li, Z and Deutscher, MP . RNase E plays an essential<br />
role in the maturation of Escherichia coli<br />
tRNA precursors. RNA 8:97-109, 2002.<br />
Li, Z, Reimers, S, Pandit, S, and Deutscher, MP .<br />
RNA quality control: degradation of defective<br />
transfer RNA. EMBO Journal 21:1132-38, 2002.<br />
Cheng, ZF and Deutscher, MP . Purification and<br />
characterization of the Escherichia coli<br />
exoribonuclease RNase R. Comparison with<br />
RNase II. Journal of Biological Chemistry<br />
277:21624-29, 2002.<br />
Zuo, Y and Deutscher, MP . The physiological<br />
role of RNase T can be explained by its unusual<br />
substrate specificity. Journal of Biological Chemistry<br />
277:29654-61, 2002.<br />
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Zuo, Y and Deutscher, MP . Mechanism of action<br />
of RNase T. I. Identification of residues required<br />
for catalysis, substrate binding, and dimerization.<br />
Journal of Biological Chemistry 277:50155-59,<br />
2002.<br />
Zuo, Y and Deutscher, MP . Mechanism of action<br />
of RNase T. II. A structural and functional model<br />
of the enzyme. Journal of Biological Chemistry<br />
277:50160-64, 2002.<br />
2003<br />
Nathanson, L, Xia, T, and Deutscher, MP .<br />
Nuclear protein synthesis: a re-evaluation. RNA<br />
9:9-13, 2003.<br />
Cheng, ZF and Deutscher, MP . Quality control of<br />
ribosomal RNA mediated by polynucleotide phosphorylase<br />
and RNase R. Proceedings of the National<br />
Academy of Sciences of the United States of<br />
America 100:6388-93, 2003.<br />
Deutscher, MP . Degradation of stable RNA in<br />
bacteria. Journal of Biological Chemistry<br />
278:45041-44, 2003.<br />
Hudder, A, Nathanson, L, and Deutscher, MP .<br />
Organization of mammalian cytoplasm. Molecular<br />
and Cellular Biology 23:9318-26, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Discovery of a new endoribonuclease, which<br />
has been called RNase G. This enzyme was<br />
shown to be essential for the maturation of the<br />
5’ terminus of E. coli 16S ribosomal RNA as<br />
part of a two-step process that also requires a<br />
second endoribonuclease, RNase E. Researchers<br />
have also identified RNase T as the enzyme that<br />
matures the 3’ terminus of 23S ribosomal<br />
RNA. Degradation of messenger RNA also was<br />
studied. They found that the enzyme<br />
oligoribonuclease is an essential component of<br />
this process, and that in its absence, small<br />
oligoribonucleotides derived from mRNA accumulate.<br />
They also have introduced the concept<br />
of quality control of stable RNA molecules.<br />
72<br />
• Development of an efficient, cell-free translation<br />
system that synthesizes protein at about 30<br />
percent of the in vivo rate. This compares with<br />
the one to two percent generally obtained in<br />
other systems. Development of this system depended<br />
on stabilization of the actin cytoskeleton<br />
during cell disruption. In a second study,<br />
they found that aminoacyl-tRNA synthetases<br />
are present in an active form in mammalian cell<br />
nuclei, and that these enzymes exist as part of a<br />
multi-enzyme complex that is analogous to, but<br />
more stable than, the cytoplasmic complex.<br />
Moreover, Dr. Deutscher’s laboratory has made<br />
the important discovery that mammalian cells<br />
are highly organized and behave like macromolecular<br />
assemblies.<br />
GENNARO D’URSO, PH.D.<br />
Assistant Professor of Molecular and<br />
Cellular Pharmacology<br />
DESCRIPTION OF RESEARCH<br />
Understanding the molecular mechanisms that<br />
control the initiation of DNA replication in<br />
eukaryotic cells is Dr. D’Urso’s main research interest.<br />
Researchers in his laboratory also are<br />
studying the checkpoint controls that prevent<br />
mitosis in the absence of a complete round of<br />
DNA synthesis or in response to DNA damage.<br />
Using the fission yeast Schizosaccharomyces pombe<br />
as a model system, they have identified genes that<br />
are required for DNA replication initiation. Most<br />
of the laboratory’s work has focused on the characterization<br />
of the genes encoding the catalytic<br />
subunit of DNA polymerase epsilon (Pol ε) and<br />
its associated subunits. Cells defective for Pol ε<br />
arrest at the G1/S boundary, indicating that this<br />
enzyme plays a critical role in the initiation step.<br />
Interestingly, the polymerization activity of this<br />
enzyme is not essential for cell viability, suggesting<br />
that Pol ε may have other roles, perhaps in<br />
the assembly of the replicative complex, that are<br />
not necessarily dependent on its ability to synthesize<br />
DNA. Studies in this laboratory on Pol ε<br />
have led to the discovery of a checkpoint control<br />
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that is activated in response to defects in DNA<br />
replication initiation. The laboratory currently is<br />
continuing efforts to identify proteins that are<br />
involved in the early steps of DNA synthesis and<br />
how these proteins may be involved in the activation<br />
of a checkpoint pathway that prevents premature<br />
entry into mitosis.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F.<br />
Control of cell polarity in fission yeast by association<br />
of Orb6p kinase with the highly conserved<br />
protein methyltransferase Skb1p. Journal of Biological<br />
Chemistry 278:25256-63, 2003.<br />
Feng, W, Rodriguez-Menocal, L, Tolun, G, and<br />
D’Urso, G. Schizosacchromyces pombe Dpb2<br />
binds to origin DNA early in S phase and is<br />
required for chromosomal DNA replication.<br />
Molecular Biology of the Cell 14:3427-36, 2003.<br />
Burhans, WC, Weinberger, J, Marchetti, MA,<br />
Ramachandran, L, D’Urso, G, and Huberman, J.<br />
Apoptosis-like yeast cell death in response to<br />
DNA damage and replication defects. Mutation<br />
Research 532:227-43, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Pol ε is required for initiation of DNA replication.<br />
These results were particularly important<br />
because Pol ε had earlier been shown to be nonessential<br />
for SV40 viral DNA replication, an<br />
extensively used model system of eukaryotic<br />
DNA replication.<br />
• Loss of the catalytic domains of this enzyme<br />
had no effect on cell viability in yeast.<br />
• These findings and observations led to an understanding<br />
of the role of Pol ε in DNA replication,<br />
and suggested that Pol ε provides multiple<br />
functions in promoting DNA replication. Recent<br />
data from this laboratory suggest that at<br />
least one of these functions is to facilitate assembly<br />
of the DNA replication initiation complex.<br />
TERACE M. FLETCHER, PH.D.<br />
Assistant Professor of Biochemistry<br />
and Molecular Biology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Fletcher’s research interests focus on chromatin<br />
structure and steroid hormone regulation of<br />
transcription, telomere chromatin structure and<br />
genomic stability, telomerase biochemistry, and<br />
mechanisms of inhibition.<br />
The eukaryotic genome is organized into<br />
complex DNA-protein macromolecular assemblies<br />
known as chromatin. Chromatin has both<br />
an architectural and regulatory function in the<br />
nucleus. Dr. Fletcher’s laboratory efforts are concentrated<br />
in two processes influenced by chromatin<br />
structure: telomere maintenance and<br />
transcription.<br />
Telomere Chromatin Structure<br />
Telomeres, specialized nucleoprotein complexes<br />
at the end of chromosomes, have a crucial role in<br />
genomic stability. Disruption of telomere structure<br />
induces cell growth arrest or death. <strong>Cancer</strong><br />
cells, unlike most normal somatic cells, maintain<br />
stable telomeres through the activation of the telomere-specific<br />
DNA polymerase, telomerase.<br />
Dr. Fletcher is particularly interested in the<br />
structural features of telomere higher-order assemblies<br />
and the mechanisms by which different<br />
telomere configurations are formed. Possible influences<br />
on telomere structure are telomerase activity,<br />
telomere length, association of telomere<br />
binding and DNA repair proteins, and DNA<br />
structure.<br />
To structurally and biochemically characterize<br />
telomere chromatin, Dr. Fletcher’s laboratory<br />
is reconstituting model telomeres in vitro. They<br />
use these model telomeres to determine recruitment<br />
of telomere binding and DNA repair proteins<br />
under certain conditions. They also are<br />
interested in the effects of telomere structure on<br />
functions such as telomerase activity and chromosome<br />
end protection.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
Finally, researchers in her laboratory are investigating<br />
the biochemical and hydrodynamic<br />
properties of telomere higher-order structures.<br />
One hydrodynamic method they will focus on is<br />
a unique agarose gel electrophoresis technique.<br />
This technique allows the investigator to analyze<br />
surface electrical charge density and solution<br />
structure of large macromolecular DNA/protein<br />
assemblies from either purified components or in<br />
complex mixtures. Dr. Fletcher and her colleagues<br />
are applying this technique to study the<br />
structure of native telomeres isolated from nuclei.<br />
Chromatin Structure and Transcription<br />
It is well established that the same promoter<br />
sequence in different chromatin contexts has<br />
diverse responses to cellular signals. The biochemical<br />
mechanisms by which nucleosomes, the<br />
fundamental units of chromatin, exert their influence<br />
are under intense investigation. The role of<br />
chromatin higher-order structures in transcriptional<br />
activation, however, is still largely unexplored.<br />
A goal of Dr. Fletcher’s research is to<br />
simultaneously analyze the structural characteristics<br />
of chromatin and transcriptional activation<br />
under various reaction conditions.<br />
Specifically, her laboratory is interested in<br />
the reciprocal relationship between transcription<br />
factors and their chromatin targets. Research efforts<br />
include reconstituting promoters and coding<br />
regions into chromatin in vitro and analyzing<br />
protein binding, chromatin remodeling, and<br />
transcriptional activation. Dr. Fletcher and her<br />
colleagues also are characterizing the solution<br />
structure of these chromatin fibers, both reconstituted<br />
in vitro and isolated from cells.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Fletcher, TM, Xiao, N, Mautino, G, Baumann,<br />
CT, Wolford, R, Warren, BS, and Hager, GL.<br />
ATP-dependent mobilization of the glucocorticoid<br />
receptor during chromatin remodeling. Molecular<br />
and Cellular Biology 22:3255-63, 2002.<br />
Lu, H, Pise-Masison, CA, Fletcher, TM, Schiltz,<br />
RL, Nagaich, AK, Radonovich, M, Hager, G,<br />
Cole, PA, and Brady, JN. Acetylation of nucleosomal<br />
histones by p300 facilitates transcription<br />
from tax-responsive human T-cell leukemia virus<br />
type 1 chromatin template. Molecular and Cellular<br />
Biology 22:4450-62, 2002.<br />
Keeton, EK, Fletcher, TM, Baumann, CT,<br />
Hager, GL, and Smith, CL. Glucocorticoid receptor<br />
domain requirements for chromatin remodeling<br />
and transcriptional activation of the<br />
mouse mammary tumor virus promoter in different<br />
nucleoprotein contexts. Journal of Biological<br />
Chemistry 277:28247-55, 2002.<br />
2003<br />
Georgel, PT, Fletcher, TM, Hager, GL, and<br />
Hansen, JC. Formation of higher-order secondary<br />
and tertiary chromatin structures by genomic<br />
mouse mammary tumor virus promoters. Genes<br />
& Development 17:1617-29, 2003.<br />
Fletcher, TM. Telomere higher-order structure<br />
and genomic instability. IUBMB Life 55:443-49,<br />
2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Obtained patent for methods and compositions<br />
for modulation and inhibition of telomerase.<br />
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ELIZABETH J. FRANZMANN, M.D.<br />
Assistant Professor of Otolaryngology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Franzmann is interested in the molecular<br />
mechanisms of head and neck squamous cell<br />
cancer (HNSCC) progression. Despite rigorous<br />
therapy using various combinations of surgery,<br />
radiation, and chemotherapy, successful treatment<br />
of head and neck cancer only occurs 50<br />
percent of the time. Because of the complexity of<br />
the head and neck, current therapy often results<br />
in facial disfigurement, speech and swallowing<br />
problems, and substantial health care costs.<br />
Screening and staging methods for HNSCC also<br />
are deficient.<br />
To better understand the molecular mechanisms<br />
that lead to HNSCC, Dr. Franzmann’s<br />
laboratory is investigating the CD44 family of<br />
alternatively spliced isoforms. Some CD44<br />
isoforms are found normally in cells. Other<br />
isoforms termed CD44 variant (CD44v) isoforms<br />
are found in tumor tissues and are associated with<br />
poor prognosis. There is particular interest in the<br />
CD44v3-containing isoforms since these<br />
isoforms contain a growth factor binding site.<br />
Preliminary work suggests that CD44v3-containing<br />
isoforms are differentially expressed in<br />
HNSCC tumors and normal tissue and may be<br />
involved in tumor cell growth. Using reverse<br />
transcriptase-polymerase chain reaction (RT-<br />
PCR), southern blot, cloning, and sequencing,<br />
the laboratory is defining CD44v3-containing<br />
isoform expression in head and neck tumor and<br />
normal tissues. The laboratory will perform immunohistochemical<br />
staining to characterize<br />
CD44v3 expression at the protein level. Transfection<br />
studies will be used to investigate the mechanisms<br />
by which these isoforms alter HNSCC cell<br />
behavior. In addition to identifying HNSCC in<br />
the early stage when treatment is much more effective,<br />
Dr. Franzmann’s laboratory is evaluating<br />
whether a salivary CD44 ELISA test is a useful<br />
screening tool for HNSCC.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,<br />
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression<br />
of tumor markers hyaluronic acid and hyaluronidase<br />
(HYAL1) in head and neck tumors.<br />
International Journal of <strong>Cancer</strong> 106:438-45, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• CD44v3-containing isoforms are found in<br />
HNSCC tumor tissues and cell lines using RT-<br />
PCR. CD44v3 and CD44v3-10 have been<br />
cloned and sequenced from HNSCC cell lines.<br />
• In a preliminary study including 26 patients<br />
with HNSCC and ten normal controls, CD44<br />
levels were significantly higher in HNSCC patient<br />
saliva compared to normal volunteer saliva.<br />
ZHIYONG HAN, PH.D.<br />
Assistant Professor of Biology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Han’s research seeks to understand how<br />
anti-cancer drugs induce apoptosis of cancer<br />
cells. His recent work focuses on how the natural<br />
product camptothecin (CPT) and its semi-synthetic<br />
derivatives such as CPT-11, 9-amino-CPT<br />
(9AC), and 9-nitro-CPT (9NC) induce apoptosis<br />
of human colon cancer cells.<br />
CPT and its derivatives are considered important<br />
anti-cancer drugs. Many aspects of the<br />
mechanism by which these drugs exert their<br />
death effect on cancer cells, however, remain<br />
largely unknown. In recent years, Dr. Han and<br />
his colleagues have used a cell model of human<br />
colon cancer to demonstrate that treatment with<br />
low doses of CPT induces senescence in the presence<br />
of a protein called p21, but apoptosis in the<br />
absence of p21. Therefore, p21 is a key determinant<br />
of the outcome of colon cancer cells treated<br />
with CPT drugs at doses that are relevant to<br />
clinical application. CPT treatment of colon cancer<br />
cells with p21 should result in disease stabili-<br />
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zation, whereas CPT treatment of p21-deficient<br />
colon cancer cells should result in rapid apoptosis<br />
and disease regression.<br />
It is well established that p21 inhibits cyclindependent<br />
kinases (cdks) and several other factors<br />
including proliferating cell nuclear antigen. Dr.<br />
Han and his colleagues hypothesize that inhibition<br />
of cdks by p21 is essential to inhibit<br />
apoptosis and induce senescence. In this context,<br />
they propose that the protein, named E2F1, is<br />
essential for apoptosis of colon cancer cells<br />
treated with CPT. According to this hypothesis,<br />
inhibition of cdks should result in activation of<br />
another protein, named retinoblastoma (Rb),<br />
which in turn, inhibits E2F1 and consequentially<br />
E2F1-dependent apoptosis. They also hypothesize<br />
that the ability of p21 to induce senescence<br />
requires a protein called STAT1. To test their hypothesis,<br />
they are currently using techniques to<br />
selectively alter the status of a cdk, E2F1, Rb, and<br />
STAT1 in human colon cancer cells. Subsequently,<br />
Dr. Han’s laboratory will investigate the<br />
role of each protein in the process of apoptosis<br />
and senescence in the colon cancer cells after<br />
CPT treatment.<br />
The information obtained from these investigations<br />
will provide better insight into the molecular<br />
pathways activated in colon cancer cells<br />
after CPT treatment and eventually lead to specific<br />
experimental designs to completely understand<br />
how CPTs affect colon cancer.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Han, Z, Wei, W, Dunaway, S, Darnowski, JW,<br />
Calabresi, P, Sedivy, J, Hendrickson, EA, Balan,<br />
KV, Pantazis, P, and Wyche, JH. Role of p21 in<br />
apoptosis and senescence of human colon cancer<br />
cells treated with camptothecin. Journal of Biological<br />
Chemistry 277(19):17154-60, 2002.<br />
2003<br />
Hu, X, Han, Z, Wyche, JH, and Hendrickson,<br />
EA. Helix 6 of tBid is necessary but not sufficient<br />
for mitochondrial binding activity. Apoptosis<br />
8:277-89, 2003.<br />
Pantazis, P, Han, Z, Balan, K, Wang, Y,<br />
and Wyche, JH. Camptothecin and 9-<br />
nitrocamptothecin (9NC) and anti-cancer,<br />
anti-HIV, and cell-differentiation agents.<br />
Development of resistance, enhancement of<br />
9NC-induced activities and combination treatments<br />
in cell and animal models. Anticancer<br />
Research 23:3623-38, 2003.<br />
Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche,<br />
JH, Han, Z, and Pantazis, P. Differential susceptibility<br />
to 9-nitrocamptothecin (9-NC)-induced<br />
apoptosis in clones derived from a human ovarian<br />
cancer cell line: possible implications in the treatment<br />
of ovarian cancer patients with 9-NC. Anticancer<br />
Drugs 14:427-36, 2003.<br />
THOMAS K. HARRIS, PH.D.<br />
Assistant Professor of Biochemistry<br />
and Molecular Biology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Harris’ research seeks to understand the<br />
structure and mechanism of both<br />
phosphoinositide-dependent protein kinase<br />
(PDK1) and protein kinase B (PKB/Akt), which<br />
are important in maintaining the growth, survival,<br />
and proliferation of numerous types of cancer<br />
cells. PDK1 and PKB/Akt are pivotal<br />
signaling enzymes and are activated by growthfactor<br />
binding events to receptor tyrosine kinases,<br />
which activate phosphatidylinositol 3-kinase (PI3K)<br />
and result in generation of the membrane-bound<br />
second messenger phosphatidylinositol 3,4,5-<br />
triphosphate. Activation of PDK1 and PKB/Akt<br />
is facilitated by recruitment of each of these<br />
proto-oncogenic enzymes to the membranebound<br />
second messenger, which binds the<br />
pleckstrin homology (PH) domain present in<br />
each of these kinases. The specific goals are to<br />
1) determine the structural bases of specificity<br />
for membrane targeting mediated by the PH<br />
domains of human PDK1 and PKB/Akt, and<br />
2) determine how binding of the PH domains to<br />
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the membrane-bound second messenger leads to<br />
the catalytic activation of their respective kinase<br />
domains.<br />
A combination of high-resolution heteronuclear<br />
multidimensional nuclear magnetic resonance<br />
(NMR) methods, nuclear Overhauser<br />
effects, and nuclear relaxation rates will be used<br />
to determine the effects that Ins(1,3,4,5)P 4<br />
binding<br />
has on the solution structures and dynamics<br />
of the bacterially expressed recombinant 15 N- and<br />
13<br />
C-isotopically labeled PH domain constructs of<br />
both human PDK1 and PKB/Akt. In addition,<br />
the recombinant 15 N-isotopically labeled PH domain<br />
constructs of both PDK1 and PKB/Akt will<br />
be spliced with their corresponding bacterially<br />
expressed recombinant unlabeled kinase domains<br />
to determine the effects that Ins(1,3,4,5)P 4<br />
binding<br />
to the PH domain has on the conformations,<br />
dynamics, and position of the PH domain with<br />
respect to the corresponding kinase domain.<br />
Finally, the modes of activation of PDK1<br />
and PKB/Akt will be elucidated by measuring the<br />
effects of Ins(1,3,4,5)P 4<br />
binding to the PH domains<br />
on the equilibrium and activation free energies<br />
associated with binding of nucleotide,<br />
metal, or protein substrates, conformational<br />
changes, and covalent catalysis. Such structural<br />
and mechanistic understanding will be useful in<br />
the rational design of potent and selective inhibitors<br />
by “linking” the free energies of binding of<br />
substrate analogs with analogs of the inositol polar<br />
head group of the phospholipid second messenger.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Harris, TK and Turner, GJ. Structural basis of<br />
perturbed pKa values of catalytic groups in enzyme<br />
active sites. IUBMB Life 53:85-98, 2002.<br />
2003<br />
Harris, TK . PDK1 and PKB/Akt: ideal targets<br />
for development of new strategies to structurebased<br />
drug design. IUBMB Life 55:117-26,<br />
2003.<br />
Gao, X, Yo, P, Keith, A, Ragan, TJ, and Harris,<br />
TK. Thermodynamically balanced inside-out<br />
(TBIO) PCR-based gene synthesis: a novel<br />
method of primer design for high-fidelity assembly<br />
of longer gene sequences. Nucleic Acids Research<br />
31:e143, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Designed and synthesized codon-optimized<br />
genes and gene constructs for PDK1 and PKB/<br />
Akt in order to optimize production of 15 N-<br />
and 13 C-isotopically labeled human PDK1 and<br />
PKB/Akt necessary for NMR structural and<br />
dynamical studies, which facilitate high-level<br />
protein production in bacteria. Researchers developed<br />
a novel thermodynamically balanced<br />
inside-out (TBIO) method of polymerase chain<br />
reaction (PCR)-based synthesis to generate the<br />
codon-optimized human kinase genes.<br />
• Filed a U.S. Patent and Trademark Office provisional<br />
patent application for the TBIO method<br />
on August 28, 2003.<br />
MARY LOU KING, PH.D.<br />
Professor of Cell Biology and Anatomy<br />
DESCRIPTION OF RESEARCH<br />
Dr. King is trying to understand how spatial<br />
patterning and cell fate is determined in the<br />
early Xenopus embryo. Researchers in her laboratory<br />
and others in the field have shown that the<br />
first step in patterning the embryo appears to be<br />
the localization of specific mRNAs to the vegetal<br />
cortex during oogenesis. These maternal mRNAs<br />
are subsequently inherited by a subset of cells in<br />
the embryo. Evidence indicates that the proteins<br />
encoded by localized mRNAs influence gene expression<br />
in a region-specific manner, leading to<br />
cellular diversification. They are actively pursuing<br />
the mechanism through which the spatial distribution<br />
of mRNAs is established and maintained.<br />
Dr. King’s laboratory has isolated seven localized<br />
mRNAs from Xenopus oocytes. Remarkably,<br />
three RNAs, Xcat-2 (related to nanos), Xdazl (in<br />
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DAZ family), and DeadSouth (in vasa family), are<br />
localized to germ plasm and are related to germ<br />
cell components in Drosophila and humans. All<br />
three of these RNAs encode RNA-binding proteins.<br />
The laboratory is interested in identifying<br />
the downstream targets of these germ cell components<br />
and their function in development. Most<br />
recently they have shown that interfering with<br />
Xdazl function eliminates or depletes primordial<br />
germ cells (PGCs) because these fail to migrate<br />
out of the endoderm. Another mRNA, VegT, encodes<br />
a T-box transcription factor. Dr. King and<br />
her colleagues have shown that maternal VegT is<br />
required for germ layer (endoderm, mesoderm,<br />
ectoderm) formation during gastrulation and specifically<br />
for endoderm identity. Experimental approaches<br />
used in these studies include the creation<br />
of dominant negatives, antisense oligos, over-expression,<br />
ectopic expression, frog transgenics,<br />
transgenics, reverse transcription-polymerase<br />
chain reaction (RT-PCR), immunocytochemistry,<br />
and in situ hybridization. A new gene, Xcat4, appears<br />
to control the cell cycle in early development, as<br />
over-expression of part of this protein completely<br />
blocks G1/S transition.<br />
Dr. King and her colleagues also have found<br />
that VegT and the germ plasm mRNAs localize by<br />
at least two different mechanisms and at different<br />
times during oogenesis. They have determined<br />
the RNA signal required for proper localization<br />
of Xcat-2 and VegT and are currently working on<br />
isolating the proteins that bind these localization<br />
signals. Their long-term goal is to characterize all<br />
seven genes as to their role in development as well<br />
as to characterize the transport systems involved<br />
in their localization.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Kloc, M, Dougherty, MT, Bilinski, S, Chan, AP,<br />
Brey, E, King, ML, Patrick, CW Jr., and Etkin,<br />
LD. Three-dimensional ultrastructural analysis of<br />
RNA distribution within germinal granules of<br />
Xenopus. Developmental Biology 241:79-93,<br />
2002.<br />
Bubunenko, M, Kress, TL, Vempati, UD,<br />
Mowry, KL, and King, ML. A consensus RNA<br />
signal that directs germ layer determinants to the<br />
vegetal cortex of Xenopus oocytes. Developmental<br />
Biology 248:82-92, 2002.<br />
2003<br />
Zhou, Y, Zhang, J, and King, ML. Xenopus<br />
ARH couples lipoprotein receptors with the AP-2<br />
complex in oocytes and embryos and is required<br />
for vitellogenesis. Journal of Biological Chemistry<br />
278:44584-92, 2003.<br />
Bruce, AE, Howley, C, Zhou, Y, Vickers, SL, Silver,<br />
LM, King, ML, and Ho, RK. The maternally<br />
expressed zebrafish T-box gene eomesodermin<br />
regulates organizer formation. Development<br />
130:5503-17, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated for the first time that a germ<br />
plasm component is required for PGC specification<br />
in a vertebrate. PGC migration out of<br />
the endoderm is a critical step in PGC differentiation<br />
and Xdazl is clearly involved. Dr. King<br />
and her colleagues want to learn more about<br />
this pathway and its requirements. They have<br />
shown that in Xenopus, germ plasm RNAs are<br />
under translational control and that most of<br />
them encode RNA binding proteins.<br />
• Observed that a single maternally expressed<br />
gene, VegT, appears to control the patterning of<br />
the Xenopus blastula. The laboratory’s studies on<br />
maternal VegT, a T-box transcription factor,<br />
have shown that it is essential for three important<br />
steps in development. VegT is required for<br />
endoderm specification, the production, activation,<br />
or delivery of the mesoderm inducer, and<br />
for maintaining the boundary between endoderm<br />
and mesoderm. Their results strongly suggest<br />
that the major mesoderm-inducing signal is<br />
a post-transcriptional event in Xenopus.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
THEODORE J. LAMPIDIS, PH.D.<br />
Professor of Cell Biology and Anatomy<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lampidis’ research has evolved from his<br />
preliminary work on the physiology and<br />
pharmacology of cultured cardiac cells. A video/<br />
electronic-computerized system was developed to<br />
monitor cardiac cell function in vitro. Using pulsating<br />
myocardial cells as a model, he focused on<br />
why the widely used anti-tumor agent, Adriamycin,<br />
affected the hearts of patients treated with<br />
this drug. This initial idea led Dr. Lampidis to<br />
study drug selectivity between certain types of<br />
tumor and normal cells and the chemical requirements<br />
of anti-cancer drugs for reduced cardiotoxicity<br />
and increased tumoricidal potency.<br />
Dr. Lampidis’ efforts then turned toward<br />
understanding the mechanisms of drug resistance<br />
to mitochondrial agents such as rhodamine 123<br />
and the structure/function requirements of various<br />
chemotherapeutic agents for recognition by<br />
p-glycoprotein-mediated multiple drug resistance<br />
(MDR). Molecular and immunochemical probes<br />
of MDR and other cellular resistance mechanisms<br />
(i.e., multi-drug resistance-related protein<br />
(MRP)), were developed in his laboratory to<br />
detect and study these phenomena. He and his<br />
colleagues found that chemical charge and<br />
lipophilicity play critical roles in determining<br />
whether anti-cancer drugs are recognized by tumor<br />
cells expressing these MDR mechanisms.<br />
As an outcome of their studies on mitochondrial<br />
agents, the researchers realized that tumor<br />
cells treated with the uncoupling agent, rhodamine<br />
123, were strikingly similar to the poorly oxygenated<br />
cancer cells located at the inner core of solid<br />
tumors. In both conditions, the cells rely exclusively<br />
on anaerobic metabolism for survival.<br />
Moreover, cells in the center of a tumor divide<br />
more slowly than outer-growing aerobic cells and<br />
consequently are more resistant to standard chemotherapeutic<br />
agents, which target the more rapidly<br />
dividing cells. Thus, by the nature of their<br />
slow growth, these tumor cells exhibit a form of<br />
MDR, which contributes significantly to chemotherapy<br />
failures in the treatment of solid tumors.<br />
Anaerobiosis, however, also provides a natural<br />
window of selectivity for agents that interfere<br />
with glycolysis. This concept forms the basis for<br />
Dr. Lampidis’ current initiative to exploit the<br />
natural selectivity that inhibitors of glycolysis<br />
should have for hypoxic cells that are slowly<br />
growing at the inner core of solid tumors. His<br />
background and work on mitochondrial localizing<br />
drugs and MDR uniquely position him to<br />
stimulate new initiatives in his laboratory in this<br />
promising area of research.<br />
A long-term goal for Dr. Lampidis is the addition<br />
of the appropriate glycolytic inhibitors<br />
(which are presently being designed and synthesized)<br />
to current clinical protocols, which may<br />
significantly improve the success rate of cancer<br />
chemotherapy. Moreover, studying how tumor<br />
cells react to combinations of oxidative phosphorylation<br />
and glycolytic inhibitors could lead to<br />
the design of future novel approaches to more<br />
successfully treat cancer.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ .<br />
Hypoxia increases tumor cell sensitivity to glycolytic<br />
inhibitors: a strategy for solid tumor therapy<br />
(Model C). Biochemical Pharmacology 64:1745-<br />
51, 2002.<br />
2003<br />
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,<br />
Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L.<br />
Overexpression of mutated MRP4 in cisplatin<br />
resistant small cell lung cancer cell line: collateral<br />
sensitivity to azidothymidine. International Journal<br />
of Oncology 23:173-9, 2003.<br />
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and<br />
Lampidis, TJ . Multidrug resistance correlates<br />
with overexpression of Muc4 but inversely with<br />
P-glycoprotein and multidrug resistance related<br />
protein in transfected human melanoma cells.<br />
Biochemical Pharmacology 65:1419-25, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 79
T U M O R C E L L B I O L O G Y P R O G R A M<br />
HIGHLIGHTS/DISCOVERIES<br />
• In osteosarcoma wild type (wt) cells treated<br />
with agents that inhibit mitochondrial oxidative<br />
phosphorylation (OXPHOS) by interacting<br />
with complexes I, III, and V of the electron<br />
transport chain in different ways—rhodamine<br />
123 (Rho-123), rotenone, oligomycin, and antimycin<br />
A—all of the agents were found to hypersensitize<br />
wt cells to the glycolytic inhibitors<br />
2-deoxyglucose (2-DG) and oxamate.<br />
• In ρ 0 cells that have lost their mitochondrial<br />
DNA and therefore cannot undergo OXPHOS,<br />
cells were found to be ten and 4.9 times more<br />
sensitive to 2-DG and oxamate, respectively,<br />
than wt cells.<br />
• Lactic acid levels, which are a measure of<br />
anaerobic metabolism, were found to be greater<br />
than 3 times higher in ρ 0 than in wt cells.<br />
Moreover, when wt cells were treated with Rho-<br />
123, lactic acid amounts increased as a function<br />
of increasing Rho-123 doses. Under similar<br />
Rho-123 treatment, ρ 0 cells did not increase<br />
their lactic aid levels. These data confirm these<br />
different cell models are similarly sensitive to<br />
glycolytic inhibitors due to their dependence on<br />
anaerobic metabolism.<br />
• These results suggest that inner core tumor cells<br />
are more dependent on glycolysis than outer<br />
growing aerobic cells, which provides a window<br />
of selectivity that can be exploited for therapeutic<br />
gain. Thus, glycolytic inhibitors could be<br />
used to specifically target the hypoxic slowgrowing<br />
cells of solid tumors and thereby increase<br />
the efficacy of current chemotherapeutic<br />
and irradiation protocols designed to kill rapidly<br />
dividing cells. Moreover, glycolytic inhibitors<br />
could be particularly useful in combination<br />
with anti-angiogenic and anti-hypoxic inducible<br />
factor (HIF) agents, which a priori, should<br />
make tumors more anaerobic.<br />
• Recently, Dr. Lampidis has provided proof of<br />
principle in two animal models of human cancer<br />
(non-small cell lung and osteosarcoma ) that<br />
the addition of the glycolytic inhibitor 2-DG<br />
(which targets the slowly growing hypoxic cells<br />
of a tumor), increases the efficacy of standard<br />
chemotherapeutic agents (which target the rapidly<br />
growing aerobic cells) in reducing tumor<br />
size and prolonging survival. In collaboration<br />
with Threshold Pharmaceuticals, the NCI, and<br />
UM/<strong>Sylvester</strong>, they have received FDA approval<br />
and are now nearing the first human trials testing<br />
his strategy.<br />
JIE LI, M.D., PH.D.<br />
Assistant Professor of Dermatology<br />
and Cutaneous Surgery<br />
DESCRIPTION OF RESEARCH<br />
Among the unanswered critical questions in<br />
cancer research is the mechanism for new<br />
blood vessel formation during tumor development,<br />
a process called tumor angiogenesis, which<br />
is important for both tumor growth and metastasis.<br />
Angiogenesis is dependent on the production<br />
and organization of the basement membrane<br />
zone, a structure underlying endothelial cells in<br />
blood vessels. Dr. Li’s current research focuses on<br />
the role of extracellular matrix laminins of major<br />
basement membrane components in tumor angiogenesis,<br />
invasion, and metastasis. The longterm<br />
goal of the study is to determine their<br />
potential in tumor diagnosis/prognosis and<br />
therapy.<br />
Dr. Li’s laboratory uses cellular and molecular<br />
biological approaches to study the function of<br />
laminins in the two most common and malignant<br />
human skin cancers: melanomas and squamous<br />
cell carcinomas (SCC). She and her<br />
colleagues have found that microvascular endothelial<br />
cells produce two laminins, laminin-8 and<br />
laminin-10. The laboratory has shown that<br />
laminin-8 has strong effects on human endothelial<br />
cell attachment, migration, and capillary tubule<br />
formation. Importantly, they have identified<br />
a high expression of laminin-10 in human melanomas<br />
while there is no expression of laminin-10<br />
in benign nevi. Significantly higher expression of<br />
laminin-10 also was detected in the basement<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
membranes of invasive SCC-masses and newly<br />
formed tumor vasculature. Strikingly, the studies<br />
demonstrated an incremental expression pattern<br />
as tumors progress from pre-malignant skin lesions<br />
of actinic keratosis to malignant SCC. The<br />
studies revealed a clear correlation between the<br />
expression level of laminin-10 and tumor invasiveness,<br />
which indicates that laminin-10 plays<br />
important roles in tumor angiogenesis and<br />
invasion.<br />
Dr. Li anticipates that her laboratory’s research<br />
will provide evidence that these two<br />
laminins play important roles in one or more key<br />
steps of tumor angiogenesis, including endothelial<br />
cell attachment, migration, basement membrane<br />
assembly, and microvascular blood vessel<br />
formation. She and her colleagues expect to establish<br />
the roles of laminins in cancer cell migration,<br />
invasion, and metastasis. These studies are<br />
expected to have profound implications for the<br />
development of novel therapies designed to target<br />
these extracellular matrix components and alter<br />
the angiogenesis and progression of cancers.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Calautti, E, Grossi, M, Mammucari, C, Aoyama,<br />
Y, Pirro, M, Ono, Y, Li, J, and Dotto, GP. Fyn<br />
tyrosine kinase is a downstream mediator of Rho/<br />
PRK2 function in keratinocyte cell-cell adhesion.<br />
Journal of Cell Biology 156:137-48, 2002.<br />
2003<br />
Li, J, Zhang, YP and Kirsner, RS. Angiogenesis in<br />
wound repair: angiogenic growth factors and the<br />
extracellular matrix. Microscopy Research and<br />
Technique 60:107-14, 2003.<br />
Vincek, V, Knowles, J, Li, J, and Nassiri, M. Expression<br />
of p63 mRNA isoforms in normal human<br />
tissue. Anticancer Research, 23:3945-48,<br />
2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that microvascular endothelial<br />
cells produce two extracellular matrix laminin<br />
proteins of laminin-8 and laminin-10, and that<br />
these two laminins play important roles in tumor<br />
angiogenesis. Angiogenesis is critical to<br />
tumor growth and metastasis and the aggressive<br />
behavior of malignant tumors is regulated by<br />
signals from their extracellular matrix environment.<br />
• Demonstrated that laminin-8 has strong effects<br />
on endothelial cell attachment, migration, and<br />
capillary tubule formation.<br />
• Identified the high expression of laminin-10<br />
in human malignant melanomas. Significantly<br />
higher expression of laminin-10 also was<br />
detected in the basement membranes of invasive<br />
SCC mass and newly formed tumor blood<br />
vessels.<br />
• Demonstrated an incremental expression pattern<br />
as tumors progress from pre-malignant<br />
skin lesions of actinic keratosis to malignant<br />
SCC. These studies revealed a clear correlation<br />
between the expression level of laminin-10 and<br />
SCC invasiveness and indicate that laminin-10<br />
plays important roles in tumor angiogenesis and<br />
invasion.<br />
Li, J, Tzu, J, Chen, Y, Zhang, YP, Nguyen, NT,<br />
Gao, J, Bradley, M, Keene, DR, Oro, AE, Miner,<br />
JH, and Marinkovich, MP. Laminin-10 is crucial<br />
for hair morphogenesis. EMBO Journal<br />
22(10):2400-10, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 81
T U M O R C E L L B I O L O G Y P R O G R A M<br />
CHIA-YANG LIU, PH.D.<br />
Assistant Professor of Ophthalmology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Liu’s research focuses on the roles of a<br />
membrane/soluble glycoprotein complex<br />
(Muc4/sialomucin complex, SMC), which is a<br />
major contributing mucin at the ocular surface<br />
and in the ocular tear film. Two specific aims<br />
were designed to examine the biological function<br />
of Muc4/SMC in vivo. The first aim is to generate<br />
Muc4/SMC knockout (KO) mice to examine<br />
its loss-of-function. Dr. Liu’s rationale is that<br />
Muc4/SMC is composed of two subunits derived<br />
from a single gene: an O-glycosylated mucin subunit<br />
ASGP-1, which has been implicated in antiadhesion<br />
phenomena at epithelial cell surfaces,<br />
and a transmembrane subunit ASGP-2, which is<br />
N-glycosylated, has two epidermal growth factorlike<br />
(EGF-like) domains, and has been implicated<br />
in ErbB2cellular signaling. Immunohistochemical<br />
analyses have shown that Muc4/SMC is expressed<br />
only in the cell layers of the superficial half of the<br />
corneal and conjunctival epithelia. These results<br />
have led the group to hypothesize that Muc4/<br />
SMC acts as an intrinsic differentiation and survival<br />
factor regulating the behavior of the cells in<br />
those epithelia through its effects on ErbB2.<br />
Muc4/SMC KO mice will be created via gene<br />
targeting. This KO mouse strain can be used to<br />
examine the biological function of Muc4/SMC<br />
and can be used as an animal model to investigate<br />
the pathogenesis of ocular surface disease such as<br />
dry eye.<br />
Dr. Liu’s second aim is to generate K14-<br />
Muc4 transgenic mice to investigate Muc4/SMC<br />
gain-of-function. His rationale is that a matured<br />
corneal epithelium contains three types of cells<br />
organized in five to six layers, which include basal<br />
cells (one layer), supra-basal cells (two layers),<br />
and superficial cells (two to three layers). These<br />
three types of cells are phenotypically distinct in<br />
terms of their proliferative activity and differentiative<br />
status. The basal cells are relatively<br />
proliferative, whereas the superficial cells are<br />
post-mitotic and become terminally differentiated.<br />
Since Muc4/SMC is expressed only in the<br />
cell layers of the superficial half of the corneal<br />
and conjunctival epithelia and Muc4/SMC can<br />
induce cellular signaling through ErbB2 receptor,<br />
it is hypothesized that Muc4/SMC-ErbB2 signaling<br />
may play an important role in regulating<br />
corneal epithelial differentiation, apoptosis, and<br />
desquamation. To test this hypothesis, an epithelial<br />
basal cell-specific promoter (K14 keratin<br />
promoter) will be used to drive Muc4/SMC expression<br />
in the K14-Muc4 transgenic (Tg) mice.<br />
It is anticipated that in the K14-Muc4 Tg, Muc4/<br />
SMC will be aberrantly over-expressed in basal<br />
corneal epithelium, which in turn will affect the<br />
corneal epithelium homeostasis. The K14-Muc4<br />
Tg will allow Dr. Liu and his colleagues to investigate<br />
the corneal epithelial cell biology. These<br />
combined studies should help to provide them<br />
with a more complete picture of the functions<br />
of Muc4/SMC at the ocular surface as well as<br />
insights into the roles of this mucin in ocular<br />
surface diseases and aberrations.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Saika, S, Ohnishi, Y, Ooshima, A, Liu, CY, and<br />
Kao, WW. Epithelial repair roles of extracellular<br />
matrix. Cornea (2 Suppl 1): S23-S29, 2002.<br />
Wang, IJ, Carlson, EC, Liu, CY, Kao, CW, Hu,<br />
FR, and Kao, WW. Cis-regulatory elements of<br />
the mouse Krt1.12 gene. Molecular Vision 8: 94-<br />
101, 2002.<br />
Austin, BA, Coulon, C, Liu, CY, Kao, WW, and<br />
Rada, JA. Altered collagen fibril formation in the<br />
sclera of lumican-deficient mice. Investigative<br />
Ophthalmology & Visual Science 43:1695-1701,<br />
2002.<br />
82<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
Paradis, H, Liu, CY, Saika, S, Muhamad, A,<br />
Doetschman, T, Good, W, Nayak, R, Laver, N,<br />
Kao, C, Kao, WW, and Gendron, R. Tubedown-<br />
1 in remodeling of the developing vitreal vasculature<br />
in vivo and regulation of capillary outgrowth<br />
in vitro. Developmental Biology 249:140-55,<br />
2002.<br />
Nikitin, AY, Liu, CY, Flesken-Nikitin, A, Chen,<br />
CF, Chen, PL, and Lee, WH. Cell lineagespecific<br />
effects associated with multiple deficiencies<br />
of tumor susceptibility genes in Msh2 -/- Rb +/-<br />
mice. <strong>Cancer</strong> Research 62: 5134-38, 2002.<br />
2003<br />
Carlson, EC, Mamiya K, Liu, CY, Gendron, RL,<br />
Birk, DE, Funderburgh, JL, and Kao, WW. Role<br />
of 41 Cys in the N-terminal domain of lumican in<br />
ex vivo collagen fibrillogenesis by cultured corneal<br />
stromal cells. Biochemical Journal 369:461-68,<br />
2003.<br />
Kao, WW and Liu, CY. The use of transgenic<br />
and knockout mice in the investigation of ocular<br />
surface cell biology. The Ocular Surface 1:5-19,<br />
2003.<br />
Saika, S, Miyamoto, T, Tanaka, S, Tanaka, T,<br />
Ishida, I, Ohnishi, Y, Ooshima, A, Ishiwata, T,<br />
Asano, G, Chikama, T, Shiraishi, A, Liu, CY,<br />
Kao, CW, and Kao, WW. Response of lens epithelial<br />
cells to injury: role of lumican in epithelial-mesenchymal<br />
transition. Investigative<br />
Ophthalmology & Visual Science 44:2094-102,<br />
2003.<br />
Liu, CY, Birk, DE, Hassell, JR, Kane, B, and<br />
Kao, WW. Keratocan-deficient mice display alterations<br />
in corneal structure. Journal of Biological<br />
Chemistry 278:21672-677, 2003.<br />
Espana, EM, Kawakita, T, Romano, A,<br />
DiPascuale, M, Smiddy, R, Liu, CY, and<br />
Tseng, SC. Stromal niche controls the plasticity<br />
of limbal and corneal epithelial differentiation in<br />
a rabbit model of recombined tissue. Investigative<br />
Ophthalmology & Visual Science 44: 5130-35,<br />
2003.<br />
Espana, EM, He, H, Kawakita, T, Di Pascuale,<br />
MA, Raju, VK, Liu, CY, and Tseng, SC. Human<br />
keratocytes cultured on amniotic membrane<br />
stroma preserve morphology and express<br />
keratocan. Investigative Ophthalmology &<br />
Visual Science 44: 5136-41, 2003.<br />
Carlson, EC, Wang, IJ, Liu, CY, Brannan, P,<br />
Kao, CW, and Kao, WW. Altered KSPG<br />
expression by keratocytes following corneal<br />
injury. Molecular Vision 9:615-23, 2003.<br />
Meek, KM, Quantock, AJ, Boote, C, Liu, CY,<br />
and Kao, WW. An X-ray diffraction investigation<br />
of corneal structure in keratocan-deficient mice.<br />
Matrix Biology 22:467-75, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Identified one targeted clone (#194) that was<br />
microinjected into the foster female mice by the<br />
gene targeting core facility at the University of<br />
Miami. Six chimeric founders have been obtained.<br />
The laboratory is in the process of<br />
breeding these chimeric mice with wt mouse to<br />
generate heterozygote mutant mice.<br />
• Plan to generate a Tg mouse model to study a<br />
mucin gene function on maintenance of epithelial<br />
tissues including mammary gland, ocular<br />
surface, and reproductive tract among others.<br />
Zhang, L, Wang, W, Hayashi, Y, Jester, JV, Birk,<br />
DE, Gao, M, Liu, CY, Kao, WW, Karin, M, and<br />
Xia, Y. A role for MEK kinase 1 in TGF-beta/<br />
activin-induced epithelium movement and embryonic<br />
eyelid closure. EMBO Journal 22: 4443-<br />
54, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 83
T U M O R C E L L B I O L O G Y P R O G R A M<br />
BALAKRISHNA L. LOKESHWAR, PH.D.<br />
Associate Professor of Urology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lokeshwar’s research focuses on the<br />
mechanism of prostate cancer metastasis<br />
and its control by novel chemotherapeutic drugs.<br />
For the last several years, Dr. Lokeshwar’s laboratory<br />
has focused on the extracellular matrix degradation<br />
and tumor metastasis. His laboratory<br />
has studied the regulation of a class of basement<br />
membrane matrix degrading enzymes called the<br />
matrix metalloproteinases (MMPs) in prostate<br />
cancer. Using cancer cell cultures established<br />
from human prostate tumor tissues obtained after<br />
prostatectomy, they showed that an imbalance<br />
exists between the levels of MMPs (overproduction)<br />
and their natural inhibitors (underproduction)<br />
in invasive prostate cancer cells. Based on<br />
this finding, they developed a hypothesis that a<br />
novel approach to control metastatic cancer is<br />
to correct the imbalance either by inhibition<br />
of secretion of MMPs or by increasing the extracellular<br />
levels of their endogenous inhibitor.<br />
Since several small synthetic inhibitors of<br />
MMPs exist, they tested the usefulness of the inhibitors<br />
using the criteria of oral bioavailability,<br />
systemic toxicity, and the ability to target bone<br />
metastasis. In their search for a suitable inhibitor,<br />
Dr. Lokeshwar’s laboratory tested a series of synthetic<br />
tetracycline analogues, which were shown<br />
to possess a strong anti-collagenase activity with<br />
little or no antibiotic activity. Researchers tested<br />
eight different chemically modified tetracyclines<br />
(CMTs) and found one of them, 6-deoxy, 6-<br />
demethyl, 4-dedimethylamino tetracycline<br />
(CMT-3, COL-3, now termed Metastat R by<br />
CollaGenix Pharmaceuticals, Newtown, Pennsylvania),<br />
to be the most promising. Oral dosing<br />
with this analogue to rats and mice-bearing metastatic<br />
prostate tumors reduced tumor growth and<br />
metastasis, with no measurable systemic toxicity.<br />
Furthermore, prophylactic dosing of the animals<br />
with the drug significantly reduced the incidence<br />
of tumor at the site of tumor cell injection. Their<br />
84<br />
demonstration of highly antimetastatic and antitumor<br />
activity of CMT-3 in a rat prostate tumor<br />
model led to its phase I clinical trial by the Developmental<br />
Therapeutics Division of the National<br />
<strong>Cancer</strong> Institute (NCI-DTP). In a recently<br />
concluded first human clinical phase I trial of<br />
COL-3, the NCI-DTP recommended COL-3 for<br />
phase II and phase III in patients with soft tissue<br />
sarcoma and advanced metastatic tumors. The<br />
University of Miami and the State University of<br />
New York at Stony Brook have jointly obtained a<br />
use patent on this drug. This finding also has<br />
generated wide interest in the use of COL-3<br />
among many investigators within and outside the<br />
University of Miami; a new patent was issued to<br />
the University for the treatment of corneal ulceration<br />
in patients with meibomian gland disease,<br />
also called ocular rosacea. Dr. Lokeshwar’s current<br />
research focuses on identifying novel plant products<br />
that have been used as folk medicine and on<br />
identifying novel combination therapies for advanced<br />
hormone-refractive prostate cancer.<br />
Dr. Lokeshwar’s research for this study also<br />
was funded by two consecutive grants from the<br />
Department of Defense Congressionally Directed<br />
Medical Program on Prostate <strong>Cancer</strong>. In its summary<br />
report to the U.S. Congress, his research was<br />
highlighted as one of the most significant outcomes<br />
of the CDMRP Prostate <strong>Cancer</strong> Program.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Dursun, D, Wang, M, Monroy, D, Li, DQ,<br />
Lokeshwar, BL , Stern, M, and Pflugfelder, SC.<br />
Experimentally induced dry eye produces ocular<br />
surface inflammation and epithelial disease. Advances<br />
in Experimental Medicine and Biology<br />
506(Pt A):647-55, 2002.<br />
Dursun, D, Wang, M, Monroy, D, Li, DQ,<br />
Lokeshwar, BL , Stern, ME, and Pflugfelder, SC.<br />
A mouse model of keratoconjunctivitis sicca. Investigative<br />
Ophthalmology & Visual Science<br />
43:632-38, 2002.<br />
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Lokeshwar, BL , Selzer, MG, Zhu, BQ, Block,<br />
NL, and Golub, LM. Inhibition of cell proliferation,<br />
invasion, tumor growth and metastasis by<br />
an oral non-antimicrobial tetracycline analog<br />
(COL-3) in a metastatic prostate cancer model.<br />
International Journal of <strong>Cancer</strong> 98:297-309,<br />
2002.<br />
Whitlatch, LW, Young, MV, Schwartz, GG,<br />
Flanagan, JN, Burnstein, KL, Lokeshwar, BL ,<br />
Rich, ES, Holick, MF, and Chen, TC. 25-<br />
Hydroxyvitamin D-1alpha-hydroxylase activity is<br />
diminished in human prostate cancer cells and is<br />
enhanced by gene transfer. Journal of Steroid Biochemistry<br />
and Molecular Biology 81:135-40,<br />
2002.<br />
2003<br />
Chen, TC, Holick, MF, Lokeshwar, BL ,<br />
Burnstein, KL, and Schwartz, GG. Evaluation of<br />
vitamin D analogs as therapeutic agents for prostate<br />
cancer. Recent Results in <strong>Cancer</strong> Research<br />
164:273-88, 2003.<br />
Li, de Q, Shang, TY, Kim, HS, Solomon, A,<br />
Lokeshwar, BL , and Pflugfelder, SC. Regulated<br />
expression of collagenases MMP-1, -8, and -13<br />
and stromelysins MMP-3, -10, and -11 by human<br />
corneal epithelial cells. Investigative Ophthalmology<br />
& Visual Science 44:2928-36, 2003.<br />
Dandekar, DS, Lokeshwar, VB, Cevallos-<br />
Arellano, E, Soloway, MS, and Lokeshwar, BL .<br />
An orally active Amazonian plant extract (BIRM)<br />
inhibits prostate cancer growth and metastasis.<br />
<strong>Cancer</strong> Chemotherapy and Pharmacology<br />
52(1):59-66, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that an imbalance exists between<br />
the levels of MMPs (overproduction) and their<br />
natural inhibitors (underproduction) in invasive<br />
prostate cancer cells.<br />
• Identified a novel, chemically modified nonantimicrobial<br />
tetracycline (COL-3) as an effective<br />
anti-metastatic drug with the potential to<br />
treat prostate cancer metastatic to bone. The<br />
NCI has completed the phase I trial of this<br />
drug and is awaiting further trials. Other novel<br />
agents are being tested in Dr. Lokeshwar’s laboratory,<br />
not only for controlling cancer, but also<br />
other chronic diseases such as chronic ocular<br />
surface inflammation. Dr. Lokeshwar’s research<br />
has brought in one patent to the University of<br />
Miami jointly with the State University of New<br />
York at Stony Brook. Meanwhile, two patents<br />
are pending on the new application of his<br />
research findings.<br />
• Identified a potential application of CMTs to<br />
treat the meibomian gland dysfunction that<br />
leads to the ocular rosacea. This was done in<br />
collaboration with Stephen C. Pfulgfelder,<br />
M.D., Baylor College of Medicine, Houston,<br />
Texas.<br />
VINATA B. LOKESHWAR, PH.D.<br />
Associate Professor of Urology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Lokeshwar’s research focuses on understanding<br />
the mechanism of cancer progression<br />
and tumor angiogenesis. Recent advances<br />
in cancer research have elucidated that the components<br />
of extracellular matrix (ECM) and<br />
ECM-degrading enzymes play a crucial role in<br />
regulating both the metastatic progression of<br />
localized tumors and tumor angiogenesis. Using<br />
bladder and prostate cancer model systems, her<br />
laboratory is trying to understand how ECM<br />
affects tumor metastasis and angiogenesis.<br />
Work in Dr. Lokeshwar’s laboratory demonstrates<br />
that an ECM component, hyaluronic acid<br />
(HA, which is a glycosaminoglycan), and its degrading<br />
enzyme, hyaluronidase (HAase), are<br />
closely associated with the biology of cancers of<br />
the bladder and prostate. They observed that elevated<br />
urinary HA and HAase levels are diagnostic<br />
indicators of bladder cancer and its grade,<br />
respectively. This finding has led to the development<br />
of a simple, noninvasive, highly sensitive,<br />
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and specific urine test (HA-HAase test; 90 percent<br />
accuracy) for detecting bladder cancer and<br />
monitoring its recurrence.<br />
Dr. Lokeshwar’s research on prostate cancer<br />
showed that immunohistochemical localization of<br />
both HA and HAase in prostate cancer tissues is<br />
greater than 85 percent accurate in predicting<br />
prognoses for prostate cancer patients and are<br />
better than CD44v6 and microvessel density.<br />
Furthermore, both HAase and the HA-HAase<br />
combination are independent predictors of prognosis.<br />
Thus, use of these markers in biopsy specimens<br />
may help clinicians make individualized<br />
treatment decisions and improve patients’<br />
prognoses.<br />
In their efforts to understand the function of<br />
tumor-derived HAase, Dr. Lokeshwar and her<br />
colleagues purified and cloned the first tumorderived<br />
HAase. They have demonstrated that this<br />
tumor-derived HAase degrades tumor-associated<br />
HA into small angiogenic fragments, which then<br />
interact with a HA receptor, RHAMM, on endothelial<br />
cells. The HA fragments and RHAMM<br />
interaction on the cell surface induces signaling<br />
events, resulting in the stimulation of endothelial<br />
cell functions, such as proliferation through the<br />
mitogen-activated protein kinase (MAPK) pathway.<br />
Endothelial cell proliferation is of key importance<br />
in tumor angiogenesis. Their recent<br />
work using anti-sense cDNA transfection strategy<br />
demonstrates that tumor-derived HAase is necessary<br />
for tumor growth and muscle invasion of<br />
bladder tumors. This is an important finding<br />
since 60 percent of bladder cancer patients with<br />
muscle invasive disease die within five years.<br />
Currently, Dr. Lokeshwar’s research focuses<br />
on three areas. First, the laboratory is comparing<br />
the efficacy of the HA-HAase test with other<br />
FDA-approved bladder tumor markers for monitoring<br />
bladder cancer recurrence. Secondly, they<br />
are testing the potential of HAase and HA-HAase<br />
to predict prognostic potential using prostate<br />
biopsy specimens. Thirdly, they are investigating<br />
the functions of HAase and HA-synthase enzymes<br />
in bladder and prostate cancer growth<br />
and progression.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lokeshwar, VB and Soloway, MS. Re: Urine<br />
based markers of urological malignancy. Journal<br />
of Urology 167:1406-07, 2002.<br />
Lokeshwar, VB , Schroeder, GL, Selzer, MG,<br />
Hautmann, SH, Posey, JT, Duncan, RC, Watson,<br />
R, Rose, L, Markowitz, S, and Soloway, MS.<br />
Bladder tumor markers for monitoring recurrence<br />
and screening comparison of hyaluronic<br />
acid-hyaluronidase and BTA-Stat tests. <strong>Cancer</strong><br />
95:61-72, 2002.<br />
Ekici, S and Lokeshwar, VB . Mesane tumoru<br />
belirleyicileri ve HA-Haase testi. Uroloji Bulteni<br />
13:133-40, 2002.<br />
Lokeshwar, VB , Schroeder, GL, Carey, RI,<br />
Soloway, MS, and Iida, N. Regulation of hyaluronidase<br />
activity by alternative mRNA splicing.<br />
Journal of Biological Chemistry 277:33654-63,<br />
2002.<br />
2003<br />
Dandekar, DS, Lokeshwar, VB , Cevallos-<br />
Arellano, E, Soloway, MS, and Lokeshwar, BL.<br />
An orally active Amazonian plant extract (BIRM)<br />
inhibits prostate cancer growth and metastasis.<br />
<strong>Cancer</strong> Chemotherapy and Pharmacology 52:59-<br />
66, 2003.<br />
Simon, MA, Lokeshwar, VB , and Soloway, MS.<br />
Current bladder cancer tests: unnecessary or beneficial?<br />
Critical Reviews in Oncology/Hematology<br />
47:91-107, 2003.<br />
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,<br />
Weed, DT, Fisher, P, and Lokeshwar, VB . Expression<br />
of tumor markers hyaluronic acid and hyaluronidase<br />
(HYAL1) in head and neck tumors.<br />
International Journal of <strong>Cancer</strong> 106:438-45,<br />
2003.<br />
Posey, JT, Soloway, MS, Ekici, S, Sofer, M,<br />
Civantos, F, Duncan, RC, and Lokeshwar, VB .<br />
Evaluation of the prognostic potential of hyaluronic<br />
acid and hyaluronidase (HYAL1) for prostate<br />
cancer. <strong>Cancer</strong> Research 63:2638-44, 2003.<br />
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HIGHLIGHTS/DISCOVERIES<br />
• Developed the HA-HAase urine test, a noninvasive<br />
test that is about 90 percent accurate in<br />
detecting bladder cancer and monitoring its<br />
recurrence.<br />
• Established that HA and HAase are greater than<br />
85 percent accurate prognostic indicators for<br />
prostate cancer.<br />
• Demonstrated the function of tumor-derived<br />
HAase in bladder tumor growth and muscle<br />
invasion.<br />
ARUN MALHOTRA, PH.D.<br />
Assistant Professor of Biochemistry and<br />
Molecular Biology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Malhotra’s research interests lie in structural<br />
biology of macromolecules involved in<br />
a variety of basic cellular functions. Three major<br />
areas of research include bacterial nucleases<br />
involved in RNA maturation and degradation,<br />
enzymes involved in RNA modification, and<br />
molecules involved in axonal guidance and<br />
neuronal development. These macromolecules<br />
are being studied using the tools of X-ray crystallography<br />
and molecular biology.<br />
Bacterial Exoribonucleases<br />
Ribonucleases play a central role in vital cellular<br />
RNA processes such as mRNA degradation and<br />
maturation and turnover of stable RNAs. Eight<br />
distinct exoribonucleases have been identified in<br />
E. coli. Of these, three (RNase T, RNase D, and<br />
oligoribonuclease) are members of a larger exonuclease<br />
superfamily (named the DEDD exonuclease<br />
family, after the four invariant acidic<br />
residues in these proteins) that includes the<br />
proofreading domains of DNA polymerases.<br />
While these proteins share similar sequence<br />
motifs, they are functionally quite different.<br />
RNase T is involved in tRNA turnover and maturation<br />
of tRNAs, 23S, and 5S rRNAs. RNase D<br />
also is involved in the maturation of tRNAs and<br />
small RNAs, but mainly as a backup enzyme.<br />
RNase D functions as a monomer, while RNase<br />
T and oligoribonuclease exist as dimers.<br />
Oligoribonuclease catalyzes the degradation of<br />
very short RNAs and is the only exoribonuclease<br />
essential for cell viability in E. coli.<br />
This project aims to obtain structures of<br />
these three exoribonucleases and to compare<br />
them to better understand differences in substrate<br />
specificities. The long-term goal of this research is<br />
to understand the structures and mechanisms of<br />
action of all exoribonucleases in a single organism;<br />
this study complements a parallel study under<br />
way in the laboratory of Murray P. Deutscher,<br />
Ph.D., (University of Miami), to completely<br />
characterize the physiological role of all the<br />
exoribonucleases in E. coli.<br />
Pseudouridine Synthases<br />
One of the most abundant post-transcriptional<br />
modifications seen in RNA is the isomerization<br />
of uridine to pseudouridine (5-ribosyluracil).<br />
While the physiological role of this modification<br />
in cells is not yet well understood, pseudouridines<br />
are often seen in functionally important regions<br />
of structural RNAs such as ribosomal RNAs,<br />
transfer RNAs, and splicing RNAs.<br />
The isomerization of uridines to pseudouridines<br />
is carried out by specialized enzymes called<br />
pseudouridine synthases. These enzymes fall into<br />
five different families; crystallographic studies in<br />
a number of laboratories have shown that three of<br />
these families have very similar structures in spite<br />
of limited sequence homologies. This project<br />
focuses on the structural studies of pseudouridine<br />
synthases from the other two families (RluD from<br />
the RluA family, and the newly discovered TruD<br />
family), in collaboration with the laboratory of E.<br />
James Ofengand, Ph.D., (University of Miami).<br />
Structural Studies of Axonal Guidance<br />
Molecules<br />
Research in this area aims to structurally characterize<br />
the interactions between ephrins and their<br />
receptors, a class of molecules involved in axonal<br />
guidance in the developing nervous system. Apart<br />
from axonal guidance, these receptors/ligands<br />
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also are involved in cell migration, patterning of<br />
the nervous system, and angiogenesis. Given their<br />
critical roles in neuronal regeneration and angiogenesis,<br />
ephrins and their receptors are excellent<br />
targets for therapeutic intervention in a variety of<br />
cancers, injuries, and diseases.<br />
Eph receptors are the largest-known family<br />
of receptor tyrosine kinases, with at least 16<br />
members identified until now. Eph receptors have<br />
an extracellular region that consists of two<br />
fibronectin motifs, a cysteine-rich region, and a<br />
conserved 180 amino acids N-terminal globular<br />
domain. The ligands for Eph receptors are the<br />
ephrins, which have eight members identified so<br />
far. These ligands share conserved core sequences<br />
of approximately 125 amino acids, including four<br />
invariant cysteine residues. Ephrin A1–A5 are<br />
anchored by glycosil-phosphatidil-inositol (GPI)<br />
to cellular membranes, while ephrin B1–B3 receptors<br />
have a transmembrane domain and an<br />
intracellular domain, which interacts with a variety<br />
of adapter and signaling molecules such as<br />
PDZ-RGS3, GRB4, JNK, and others.<br />
The two classes of ephrins and their receptors,<br />
A and B, are defined by sequence homologies,<br />
mechanism of membrane anchorage, and by preferential<br />
binding of the ligands to their receptors.<br />
While within the same class, the ligand-receptor<br />
binding tends to be nonspecific; there is no cross<br />
interaction between the two classes, except Eph<br />
A4, which binds some of the B class ephrins.<br />
Ephrins-Eph interactions also are intriguing because<br />
these molecules often display bidirectional<br />
signaling: a forward signal (binding of ephrins to<br />
Eph receptor determines a response in a cell or<br />
axon) and a reverse/downstream signal (binding<br />
of Eph receptor to ephrin causes a change in the<br />
cell or axon to which ephrin molecule is bound).<br />
This research aims to better understand the<br />
structural basis of ephrin/Eph ligand-receptor binding<br />
and specificity by crystallographic studies of<br />
the extracellular domains of several of these molecules.<br />
Residues identified as being critical for ephrin/<br />
Eph specificity also will be tested functionally using<br />
mutational approaches, in collaboration with the<br />
laboratory of Daniel J. Leibl, Ph.D., at The Miami<br />
Project to Cure Paralysis, University of Miami.<br />
88<br />
SELECTED PUBLICATIONS<br />
2003<br />
Everhart, D, Reiller, E, Mirzoian, A, McIntosh,<br />
JM, Malhotra, A, and Luetje, CW. Identification<br />
of residues that confer a-conotoxin-PnIA sensitivity<br />
on the α3 subunit of neuronal nicotinic acetylcholine<br />
receptors. Journal of Pharmacology<br />
and Experimental Therapeutics 306: 664-70,<br />
2003.<br />
Del Campo, M, Ofengand, J, and Malhotra, A.<br />
Purification and crystallization of Escherichia coli<br />
pseudouridine synthase RluD. Acta<br />
Crystallographica D, 59:1871-73, 2003.<br />
Del Campo, M, Ofengand, J, and Malhotra, A.<br />
Crystal structure of the catalytic domain of<br />
RluD, the only rRNA pseudouridine synthase<br />
required for normal growth of Escherichia coli.<br />
RNA 10:231-39, 2003.<br />
AKILA MAYEDA, PH.D.<br />
Assistant Professor of Biochemistry<br />
and Molecular Biology<br />
DESCRIPTION OF RESEARCH<br />
The human genome project has underscored<br />
the critical importance of alternative premRNA<br />
splicing for expressing a full proteome<br />
with its complexity from an unexpectedly small<br />
set of genes, i.e., less than 30,000 by most recent<br />
estimation.<br />
Researchers in Dr. Mayeda’s laboratory are<br />
working to understand the basic mechanisms of<br />
splicing regulation in human genes. Three main<br />
projects are ongoing: 1) to study the function of<br />
the human splicing activator RNPS1, which is<br />
also an important factor to link splicing and the<br />
post-splicing process, e.g., nonsense-mediated<br />
mRNA decay (NMD); 2) to study the function<br />
of human HMGA1a, which is the hypoxia-inducible<br />
factor causing aberrant splicing of<br />
Presenilin-2 (PS2) pre-mRNA. PS2 is one of the<br />
genes linked to Alzheimer’s disease (AD); and<br />
3) to study the splicing mechanisms of extremely<br />
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long introns using the dystrophin (DMD) gene.<br />
Many cases of Duchenne muscular dystrophy<br />
are caused by splicing defects of the DMD gene<br />
transcript.<br />
The high prevalence of clinically relevant<br />
mutations that affect splicing in genetic diseases<br />
and cancer has become increasingly apparent.<br />
The aberrant splicing patterns of many genes are<br />
involved in the establishment or maintenance of<br />
the transformed phenotype or in the progression<br />
to malignancy of cancer cells. Thus, Dr. Mayeda’s<br />
research will advance the basic understanding of<br />
the regulation of pre-mRNA splicing, which will<br />
undoubtedly have a long-term impact on public<br />
human health.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Hou, VC, Lersch, R, Gee, SL, Ponthier, JL, Lo,<br />
AJ, Wu, M, Turck, CW, Koury, M, Krainer, AR,<br />
Mayeda, A, and Conboy, JG. Decrease in<br />
hnRNP A/B expression during erythropoiesis<br />
mediates a pre-mRNA splicing switch. EMBO<br />
Journal 21:6195-204, 2002.<br />
2003<br />
Liu, X, Mayeda, A, Tao, M, and Zheng, Z-M.<br />
Exonic splicing enhancer-dependent selection of<br />
bovine papillomavirus type 1 nucleotide 3225 3’<br />
splice site can be rescued in a cell lacking splicing<br />
factor ASF/SF2 through activation of the<br />
phosphatidylinositol 3-kinase/Akt pathway. Journal<br />
of Virology 77:2105–15, 2003.<br />
Domsic, JK, Wang, Y, Mayeda, A, Krainer, AR,<br />
and Stoltzfus, CM. HIV-1 hnRNP A/B-dependent<br />
exonic splicing silencer ESSV antagonizes<br />
binding of U2AF65 to viral polypyrimidine<br />
tracts. Molecular and Cellular Biology 23:8762-<br />
72, 2003.<br />
Hu, D, Mayeda, A, Trembley, JH, Lahti, JM, and<br />
Kidd, VJ. CDK11 complexes promote premRNA<br />
splicing. Journal of Biological Chemistry<br />
278:8623–29, 2003.<br />
Manabe, T, Katayama, T, Sato, N, Gomi, F,<br />
Hitomi, J, Yanagida, T, Kudo, T, Honda, A,<br />
Mori, Y, Matsuzaki, S, Imaizumi, K, Mayeda, A,<br />
and Tohyama, M. Induced HMGAIa expression<br />
causes aberrant splicing of presenilin-2 premRNA<br />
in sporadic Alzheimer’s disease. Cell<br />
Death and Differentiation 10:698–708, 2003.<br />
Amada, N, Tezuka, T, Mayeda, A, Araki, K,<br />
Takei, N, Todokoro, K, and Nawa, H. A novel<br />
rat orthologue and homologue for the Drosophila<br />
crooked neck gene in neural stem cells and their<br />
immediate descendants. Journal of Biochemistry<br />
135:615–623, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that splicing activator RNPS1 is<br />
incorporated in the early splicing complex,<br />
stimulates formation of the ATP-dependent<br />
splicing complex, and subsequently increases<br />
generation of both intermediate and final<br />
spliced products.<br />
• Discovered experimental evidence supporting a<br />
novel mechanism, termed ‘nested intron splicing’,<br />
i.e., multiple splicing of internal nested<br />
introns preceding the eventual splicing at the<br />
authentic 5’ and 3’ splice sites by using the human<br />
DMD gene.<br />
CARLOS T. MORAES, PH.D.<br />
Associate Professor of Neurology<br />
DESCRIPTION OF RESEARCH<br />
Although mitochondrial genetics of yeast and<br />
trypanosomes has been explored extensively<br />
in the last 20 years, the study of human mitochondrial<br />
DNA (mtDNA) gained momentum in<br />
1988 with the discovery of diseases associated<br />
with mtDNA mutations. The human mtDNA is<br />
a compact circular genome (16.6 kb) coding for<br />
components of the ATP-producing oxidative<br />
phosphorylation system. Because mtDNA-coded<br />
polypeptides are synthesized in mitochondrialspecific<br />
ribosomes, the mtDNA also codes for a<br />
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set of rRNAs and tRNAs necessary for intraorganelle<br />
translation. The contribution of the<br />
mitochondrial genome to cellular respiration,<br />
though vital, is not sufficient. Dozens of nuclearcoded<br />
proteins synthesized in the cytoplasm are<br />
imported into mitochondria and assembled with<br />
mitochondrially synthesized proteins to form a<br />
functional oxidative phosphorylation system.<br />
Recently, defects in mitochondrial function<br />
also have been associated with some forms of<br />
tumors. Mutations in the mtDNA also have<br />
been described in a large number of tumors.<br />
Dr. Moraes currently is studying the potential<br />
role of these mutations in cell signaling and invasion.<br />
Mitochondria also are major players in programmed<br />
cell death, an important determinant<br />
of tumorigenesis. A number of anti- and proapoptotic<br />
factors seem to mediate their functions<br />
in association with mitochondrial membranes.<br />
Dr. Moraes and his colleagues also are exploring<br />
the role of cytochrome c in stimulating apoposis.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Moraes, CT, Srivastava, S, Kirkinezos, I, Oca-<br />
Cossio, J, van Waveren, C, Woischnick, M, and<br />
Diaz, F. Mitochondrial DNA structure and function.<br />
International Review of Neurobiology 53:3-<br />
23, 2002.<br />
Moraes, CT. Studying mitochondria of animal<br />
cells. Methods 26:291, 2002.<br />
Woischnik, M and Moraes, CT. Pattern of organization<br />
of human mitochondrial pseudogenes in<br />
the nuclear genome. Genome Research 12:885-<br />
93, 2002.<br />
Lanza, RP, Chung, HY, Yoo, JJ, Wettstein, PJ,<br />
Blackwell, C, Borson, N, Hofmeister, E, Schuch,<br />
G, Soker, S, Moraes, CT, West, MD, and Atala,<br />
A. Generation of histocompatible tissues using<br />
nuclear transplantation. Nature Biotechnology<br />
20:689-96, 2002.<br />
Diaz, F, Bayona-Bafaluy, MP, Rana, M, Mora, M,<br />
Hao, H, and Moraes, CT. Human mitochondrial<br />
DNA with large deletions repopulates organelles<br />
faster than full-length genomes under relaxed<br />
copy number control. Nucleic Acids Research<br />
30:4626-33, 2002.<br />
2003<br />
Manfredi, G, Kwong, JQ, Oca-Cossio, JA,<br />
Woischnik, M, Gajewski, CD, Martushova, K,<br />
D’Aurelio, M, Friedlich, AL, and Moraes, CT.<br />
BCL-2 improves oxidative phosphorylation and<br />
modulates adenine nucleotide translocation in<br />
mitochondria of cells harboring mutant mtDNA.<br />
Journal of Biological Chemistry 278:5639-45,<br />
2003.<br />
Bacman, SR, Atencio, DP, and Moraes, CT. Decreased<br />
mitochondrial tRNALys steady-state levels<br />
and aminoacylation are associated with the<br />
pathogenic G8313A mitochondrial DNA mutation.<br />
Biochemical Journal 374:131-36, 2003.<br />
Bayona-Bafaluy, MP, Manfredi, G, and Moraes,<br />
CT. A chemical enucleation method for the<br />
transfer of mitochondrial DNA to rho(o) cells.<br />
Nucleic Acids Research 31:e98, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Discovered that cells with defective mitochondrial<br />
respiration can be more resistant to cell<br />
death. This is a counterintuitive concept since it<br />
was previously thought that the less energy a<br />
cell has, the easier it is to kill it. Programmed<br />
cell death, however, does require a considerable<br />
amount of ATP (energy) to occur. These findings<br />
may explain the presence of mtDNA mutations<br />
in some cancers.<br />
• Demonstrated that mitochondrial defects<br />
stimulate the production of metalloproteases,<br />
which in turn, promote tissue invasion.<br />
90<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
AYMEE PEREZ, PH.D.<br />
Assistant Professor of<br />
Cell Biology and Anatomy<br />
DESCRIPTION OF RESEARCH<br />
Sialomucin complex (SMC/Muc4) is a<br />
heterodimeric glycoprotein complex consisting<br />
of a mucin subunit ascites sialoglycoprotein-1<br />
(ASGP-1) and a transmembrane subunit (ASGP-<br />
2), which is aberrantly expressed on the surface of<br />
a variety of tumor cells. Muc4 is transcribed from<br />
a single gene, translated into a large polypeptide<br />
precursor, and further processed to yield the mature<br />
ASGP-1/ASGP-2 complex. Muc4 has complex<br />
spatial and temporal expression patterns in<br />
the normal rat, suggesting that it has complex<br />
regulatory mechanisms.<br />
Muc4 is expressed in most vulnerable epithelia<br />
and is presumed to serve as a protective agent<br />
whose mucin subunit provides a steric block to<br />
the access of noxious agents such as bacteria or<br />
viruses. In many of these epithelia, such as the<br />
airway and cervix/vagina, Muc4 is constitutively<br />
expressed. Two notable exceptions are the mammary<br />
gland and uterus. In the uterus, Muc4 is<br />
expressed in the virgin animal, but down-regulated<br />
hormonally at the transcript level to repress<br />
Muc4 expression at the time of blastocyst implantation.<br />
Regulation in the mammary gland is<br />
even more complex and includes transcriptional<br />
and post-transcriptional levels of regulation.<br />
Dr. Perez has two ongoing projects in her<br />
laboratory. The first project investigates the<br />
mechanisms involved in the transcriptional regulation<br />
of Muc4 by prolactin and the transcription<br />
factor PEA3. The second project focuses on the<br />
post-transcriptional regulatory mechanisms involved<br />
in repressing Muc4 in the virgin animal,<br />
which are overridden during mid-pregnancy and<br />
tumor progression. Dr. Perez and her colleagues<br />
believe that these regulatory mechanisms provide<br />
a key to understanding the function of Muc4 in<br />
both the normal gland and its tumors.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Carraway, KL, Perez, A, Idris, N, Jepson, S,<br />
Arango, M, Komatsu, M, Haq, B, Price-Schiavi,<br />
SA, Zhang, J, and Carraway, CA. Muc4/<br />
sialomucin complex, the intramembrane ErbB2<br />
ligand, in cancer and epithelia: to protect and to<br />
survive. Progress in Nucleic Acid Research and<br />
Molecular Biology 71:149-85, 2002.<br />
2003<br />
Perez, A, Barco, R, Fernandez, I, Price-Schiavi,<br />
SA, and Carraway, KL. PEA3 transactivates the<br />
Muc4/Sialomucin Complex promoter in mammary<br />
epithelial and tumor cells. Journal of Biological<br />
Chemistry 278:36942-52, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that up-regulation of the Muc4<br />
gene in the 13762 sublines of the rat mammary<br />
adenocarcinoma correlates with the overexpression<br />
of transcription factor PEA3 and the receptor<br />
tyrosine kinase ErbB2. PEA3 is capable of<br />
transactivating the Muc4 promoter in a dosedependent<br />
manner via direct attachment to a<br />
PEA3 binding site. Ras and MEKK1 kinases<br />
potentiate transcriptional activation of Muc4 by<br />
PEA3. These data suggest that expression of<br />
PEA3 in mammary tumors leads to up-regulation<br />
of MUC4 transcription, the gene product<br />
of which may contribute to the metastatic<br />
potential of mammary tumors.<br />
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PEDRO J. I. SALAS, M.D., PH.D.<br />
Associate Professor of Cell Biology<br />
and Anatomy<br />
DESCRIPTION OF RESEARCH<br />
Centrosomes are an essential piece of the mitotic<br />
machinery. In polarized epithelial cells,<br />
centrosomes and other non-centrosomal microtubule<br />
organizing centers (MTOC) are distributed<br />
in a subapical localization. During mitosis, centrosomes<br />
migrate to the lateral domain, from<br />
where they organize the spindle. This orientation<br />
of the spindle is crucial for the maintenance of<br />
epithelial polarity since it determines that the cytokinesis<br />
will proceed in a plane perpendicular to<br />
the plane of the epithelial layer. Likewise, the polarization<br />
of MTOCs during interphase is essential<br />
to the polarization because it ensures that the<br />
minus ends of microtubules will be aligned under<br />
the apical domain.<br />
Dr. Salas’ research has demonstrated that<br />
centrosomes and non-centrosomal MTOCs colocalize<br />
with the apical intermediate filament (IF)<br />
cytoskeleton by using high-resolution confocal<br />
microscopy, near-neighbor deconvolution, and<br />
3D image reconstruction. At the electron microscopy<br />
level, co-localization indicated that<br />
pericentriolar material containing g-tubulin and<br />
the cytokeratin (CK) 19 intermediate filaments<br />
approach up to 10 nm. Using sonication, homogenization,<br />
and immunoprecipitation coupled<br />
with immunoblot, his laboratory also demonstrated<br />
that CKs 18 and 19 co-immunoprecipitate<br />
with g-tubulin in fragments that cannot<br />
sustain physical trapping. The down-regulation of<br />
CK19 IF using anti-sense oligonucelotides resulted<br />
in changes in localization of the centrosomes.<br />
The analysis of the sonication<br />
fragments indicated that only a few proteins<br />
other than CKs and g-tubulin are present, so that<br />
two potential candidates identified by yeast twohybrid<br />
and MS-MS microsequencing to fulfill<br />
the role of the “glue” attaching centrosomes, are<br />
now under consideration. Interestingly, one of<br />
those proteins is phosphorylated by p34cdc2. Because<br />
the IF do not depolymerize during mitosis<br />
92<br />
in epithelial cells, the attachment of centrosomes<br />
to IF must be necessarily broken at the onset of<br />
mitosis. Current laboratory projects include the<br />
isolation and identification of the protein(s) involved<br />
in the apical attachment of centrosomes to<br />
IF and their function during mitosis. Theoretically,<br />
a manipulation of this mechanism may halt<br />
the cell cycle in actively dividing epithelial cells.<br />
In addition, the relevance of this mechanism during<br />
ischemia or ATP depletion also is under<br />
investigation.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Yang, X, Salas, PJ , Pham, TV, Wasserlauf, BJ,<br />
Smets, MJ, Myerburg, RJ, Gelband, H,<br />
Hoffman, BF, and Bassett, AL. Cytoskeletal actin<br />
microfilaments and the transient outward potassium<br />
current in hypertrophied rat ventriculocytes.<br />
Journal of Physiology 541:411-21, 2002.<br />
Figueroa, Y, Wald, FA, and Salas, PJ . p34cdc2-<br />
mediated phosphorylation mobilizes microtubule-organizing<br />
centers from the apical<br />
intermediate filament scaffold in CACO-2 epithelial<br />
cells. Journal of Biological Chemistry<br />
277:37848-54, 2002.<br />
2003<br />
Ramsauer, VP, Carothers Carraway, CA, Salas,<br />
PJ, and Carraway, KL. MUC4/Sialomucin complex,<br />
the intramembrane ErbB2 ligand, translocates<br />
ErbB2 to the apical surface in polarized<br />
epithelial cells. Journal of Biological Chemistry<br />
278:30142-47, 2003.<br />
Ameen, NA, Marino, C, and Salas, PJ . cAMPdependent<br />
exocytosis and vesicle traffic regulate<br />
CFTR and fluid transport in rat jejunum in vivo.<br />
American Journal of Physiology Cell Physiology<br />
284:C429-38, 2003.<br />
Wald, FA, Figueroa, Y, Oriolo, AS, and Salas, PJ .<br />
Membrane repolarization is delayed in proximal<br />
tubules after ischemia-reperfusion: possible role<br />
of microtubule-organizing centers. American<br />
Journal of Physiology Renal Physiology<br />
285:F230-40, 2003.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
HIGHLIGHTS/DISCOVERIES<br />
• Observed the attachment of centrosomes to IF.<br />
Although the implications of the mechanism of<br />
detachment during mitosis are still to be assessed,<br />
this may be relevant for cancer therapy.<br />
OLUWATOYIN SHONUKAN, M.D.<br />
Assistant Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Malignant melanoma arises from the melanocytes,<br />
cells that originate in the neural<br />
crest. Normal melanocyte development in the<br />
neural crest and subsequent migration of the<br />
melanocyte precursors into the skin require<br />
trophic signals from the neurotrophin family<br />
of growth factors. With terminal differentiation,<br />
melanocytes lose expression of neurotrophin<br />
receptors. Following transformation, however,<br />
melanoma cells aberrantly express the receptors<br />
for the neurotrophins, with more advanced stages<br />
of the disease being more likely to express the<br />
neurotrophin receptors than the earlier stages.<br />
Dr. Shonukan’s research discovered that the<br />
melanoma cells also express several members of<br />
the neurotrophin growth factor family, thus<br />
suggesting that the neurotrophin/neurotrophin<br />
receptor system may be involved in the mediation<br />
of melanoma progression. The focus of her<br />
laboratory’s research is to understand the role<br />
of the neurotrophins and their receptors in the<br />
mediation of tumor progression in malignant<br />
melanoma.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Shonukan, O, Bagayogo, I, McCrea, P, Chao, M,<br />
and Hempstead, B. Neurotrophin-induced melanoma<br />
cell migration is mediated through the actin-bundling<br />
protein fascin. Oncogene<br />
22:3616-23, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Nerve growth factor (NGF), the prototypic<br />
member of this family of growth factors, mediates<br />
the invasiveness of melanoma cells in vitro<br />
by inducing the coupling of the intracellular<br />
domain of the p75 neurotrophin receptor with<br />
the actin cytoskeleton.<br />
• Neurotrophin-induced melanoma invasiveness<br />
is mediated by signals generated through PI-3<br />
kinase.<br />
• NGF induces the disruption of cadherin-mediated<br />
cell-cell adhesion, thereby permitting melanoma<br />
cells to dissociate from the keratinocytes<br />
in the epidermis and invade the dermis, from<br />
whence they metastasize to distant sites. Dr.<br />
Shonukan’s ongoing research efforts include<br />
identifying the components of this pathway in<br />
order to identify therapeutic targets.<br />
RAKESH SINGAL, M.D.<br />
Associate Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Singal’s research focuses on the mechanisms<br />
that inactivate certain tumor-suppressor<br />
genes in prostate cancer. A common mode of<br />
such inactivation involves a modification (methylation)<br />
in DNA. By understanding how genes are<br />
silenced, treatments can be developed to activate<br />
them and thereby prevent the development and/<br />
or progression of prostate cancer. Researchers in<br />
Dr. Singal’s laboratory also are studying methylation<br />
of selected genes as a diagnostic and prognostic<br />
marker in prostate cancer.<br />
The present screening techniques for prostate<br />
cancer are very inefficient, and two out of three<br />
patients undergo prostate biopsy unnecessarily<br />
to detect cancer. <strong>Cancer</strong> patients often have a<br />
small amount of DNA circulating in their serum,<br />
thought to be released from the cancer cells. Dr.<br />
Singal’s laboratory has shown that certain methylated<br />
genes are present at a substantially higher<br />
percentage in prostate cancer tissue but not in<br />
benign prostatic conditions. Researchers are<br />
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investigating if these methylated genes can be<br />
detected in serum DNA in patients with prostate<br />
cancer. If so, this test can be used as a part of<br />
prostate cancer screening, saving unnecessary<br />
prostate biopsies.<br />
DNA methylation plays a role during development<br />
by regulating gene expression. Another<br />
project in Dr. Singal’s laboratory focuses on understanding<br />
the role of methylation in regulating<br />
the expression of genes responsible for hemoglobin<br />
synthesis. Understanding the contribution of<br />
methylation to globin gene expression and the<br />
mechanisms involved will lead to the development<br />
of safe and effective therapies for globin gene disorders<br />
like thalassemia and sickle cell anemia.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Singal, R, vanWert, JM, and Ferdinand, L Jr.<br />
Methylation of alpha-type embryonic globin gene<br />
alpha pi represses transcription in primary erythroid<br />
cells. Blood 100:4217-22, 2002.<br />
Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and<br />
Ginder, GD. Methylation of promoter proximal<br />
transcribed sequences of an embryonic globin<br />
gene inhibits transcription in primary erythroid<br />
cells and promotes formation of a cell type-specific<br />
methyl cytosine binding complex. Journal of<br />
Biological Chemistry 277:1897-1905, 2002.<br />
Noss, KR, Singal, R, and Grimes, SR. Methylation<br />
state of the prostate specific membrane antigen<br />
(PSMA) CpG island in prostate cancer cell<br />
lines. Anticancer Research 22:1505-11, 2002.<br />
2003<br />
Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal,<br />
R, and Gill, S. Gynecomastia attributable to human<br />
chorionic gonadotropin-secreting giant cell<br />
carcinoma of lung. Endocrine Practice 9:233-35,<br />
2003.<br />
JOYCE M. SLINGERLAND, M.D., PH.D.,<br />
F.P.R.C. (C)<br />
Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Slingerland’s research investigates how<br />
cancers escape negative growth controls. Following<br />
her discovery of a key inhibitor of cell<br />
cycle progression, p27, Dr. Slingerland and her<br />
colleagues went on to demonstrate that p27 levels<br />
are reduced in up to 60 percent of common human<br />
cancers (breast, prostate, lung, ovarian, and<br />
others), in association with poor patient prognosis.<br />
Dr. Slingerland showed that the therapeutic<br />
effect of antiestrogens in breast cancer requires<br />
the cyclin-dependent kinase (cdk) inhibitors p21<br />
and p27 to mediate growth arrest. Oncogenic<br />
activation of mitogenic signaling via the mitogenactivated<br />
protein kinase (MAPK) pathway deregulates<br />
p27 function, causing tamoxifen resistance<br />
in breast cancer. She provided key insights demonstrating<br />
the role of cell cycle inhibitors p15 and<br />
p27 as mediators of G1 arrest by transforming<br />
growth factor-beta (TGF-β) and demonstrated<br />
that cancer cells lose responsiveness to this<br />
growth inhibitory cytokine through loss or deregulation<br />
of p27. In a recent publication, her<br />
laboratory demonstrated that checkpoint loss<br />
during cancer progression makes p27 an essential<br />
mediator of arrest. They also showed that functional<br />
inactivation of p27 in human cancers can<br />
either occur through accelerated p27 degradation<br />
or through altered p27 phosphorylation leading to<br />
p27 mislocalization. The laboratory recently<br />
showed that activation of mitogenic signaling<br />
via the receptor tyrosine kinases and the<br />
phosphoinositol 3’ kinase pathway alters p27<br />
phosphorylation and function and the protein<br />
accumulates in the cytoplasm away from its targets<br />
in the nucleus. This work links oncogene<br />
activation with loss or inactivation of the cell<br />
cycle inhibitor, p27, elucidating a major mechanism<br />
of loss of growth control in cancer progression.<br />
Dr. Slingerland’s laboratory also is investigating<br />
the cause of aggressive estrogen receptor<br />
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negative (ER-) breast cancers. Her laboratory has<br />
found that oncogenic receptor tyrosine kinase<br />
and cSrc activation may not only activate mitogenic<br />
signaling leading to aggressive proliferation, it<br />
may also lead to loss of detectable ER protein in<br />
ER- breast cancers. One-third of newly diagnosed<br />
breast cancers are ER- and have a poor prognosis.<br />
Investigation of mechanisms underlying loss of<br />
ER expression showed that all of 70 primary ERbreast<br />
cancers expressed ER mRNA. Src or<br />
proteasome inhibition increased ER levels and<br />
Src transfection stimulated both ligand-activated<br />
ER transcriptional activity and ER proteolysis.<br />
Cotransfection of Her2 and Src reduced ER levels<br />
further. ER- primary breast cancers and cell lines<br />
showed increased Src activity compared to ER+<br />
cancers and cell lines, and the ER protein half-life<br />
was reduced in ER- breast cancer lines. These<br />
data support a model in which Her2 and cSrc<br />
cooperate with liganded ER to promote both ER<br />
dependent transcription and transcription linked<br />
ER proteolysis.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Donovan, JC, Rothenstein, JM, and Slingerland,<br />
JM. Non-malignant and tumor-derived cells differ<br />
in their requirement for p27Kip1 in transforming<br />
growth factor-beta-mediated G1 arrest.<br />
Journal of Biological Chemistry 277:41686-92,<br />
2002.<br />
Liang, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R,<br />
Connor, MK, Han, K, Lee, JH, Ciarallo, S,<br />
Catzavelos, C, Beniston, R, Franssen, E, and<br />
Slingerland, JM . PKB/Akt phosphorylates p27,<br />
impairs nuclear import of p27 and opposes p27-<br />
mediated G1 arrest. Nature Medicine 8:1153-60,<br />
2002.<br />
Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH,<br />
Kotchetkov, R, Sandhu, C, Milic, A, and<br />
Slingerland, JM . Altered p27(Kip1) phosphorylation,<br />
localization, and function in human epithelial<br />
cells resistant to transforming growth<br />
factor beta-mediated G(1) arrest. Molecular and<br />
Cellular Biology 22:2993-3002, 2002.<br />
2003<br />
Connor, MK, Kotchetkov, R, Cariou, S, Resch,<br />
A, Lupetti, R, Beniston, RG, Melchior, F,<br />
Hengst, L, and Slingerland, JM . CRM1/Ranmediated<br />
nuclear export of p27(Kip1) involves a<br />
nuclear export signal and links p27 export and<br />
proteolysis. Molecular Biology of the Cell<br />
14:201-13, 2003.<br />
Liang, J and Slingerland, JM . Multiple roles of<br />
the PI3K/PKB (Akt) pathway in cell cycle progression.<br />
Cell Cycle 2:339-45, 2003.<br />
FULVIA VERDE, PH.D.<br />
Assistant Professor of Molecular and<br />
Cellular Pharmacology<br />
DESCRIPTION OF RESEARCH<br />
Control of Cell Morphogenesis<br />
Dr. Verde’s research seeks to understand the<br />
molecular basis of cell morphogenesis in eukaryotic<br />
cells and its coordination to cell proliferation.<br />
To this end, Dr. Verde and her colleagues<br />
have investigated the function of Orb6, a conserved<br />
protein kinase that is required for maintenance<br />
of cell polarity and regulation of the cell<br />
cycle. They have identified six proteins that<br />
physically interact with Orb6 and established<br />
their role in the control of Orb6 function. Five of<br />
these proteins are conserved in human cells.<br />
These factors are involved in Orb6 activity regulation,<br />
are implicated in the control of Orb6 intracellular<br />
localization, or function as substrate<br />
effectors of Orb6 kinase in the control of cell<br />
morphology and the cell cycle.<br />
Furthermore, Dr. Verde’s laboratory has been<br />
working with Tea1, a microtubule-associated protein,<br />
that functions as a marker for cell polarity<br />
and shows similarity to human ERM (ezrin,<br />
radixin, and moesin) proteins. They have identified<br />
several proteins that interact with Tea1 by 2-<br />
hybrid screening. One of these proteins has been<br />
recently shown to be essential for spatial organi-<br />
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zation of microtubule dynamics. These findings<br />
are important because little is known about the<br />
mechanism of microtubule-dependent cell morphogenesis.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F.<br />
Control of cell polarity in fission yeast by association<br />
of Orb6p kinase with the highly conserved<br />
protein methyltransferase Skb1p. Journal of Biological<br />
Chemistry 278:25256-63, 2003.<br />
Hou, MC, Wiley, DJ, Verde, F, and McCollum,<br />
D. Mob2p interacts with the protein kinase<br />
Orb6p to promote coordination of cell polarity<br />
with cell cycle progression. Journal of Cellular<br />
Science 116:125-35, 2003.<br />
Kim, H, Yang, P, Catanuto, P, Verde, F, Lai, H,<br />
Du, H, Chang, F, and Marcus, S. The kelch repeat<br />
protein, Tea1, is a potential substrate target<br />
of the p21-activated kinase, Shk1, in the fission<br />
yeast, Schizosaccharomyces pombe. Journal of Biological<br />
Chemistry 278:30074-82, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that Bot1 may function as a molecular<br />
bridge between Tea1, a microtubuleassociated<br />
protein required to establish cell<br />
polarity and Orb6, a conserved protein kinase<br />
related to mammalian Rho kinase and myotonic<br />
dystrophy kinase. These findings suggest<br />
that one of the effectors of Orb6 kinase is the<br />
formin For3p that functions in the control of<br />
actin cable polymerization. They also offer insight<br />
into the hierarchy of events that lead to<br />
polarized cell growth and in the mechanisms of<br />
microtubule-dependent cell polarity control.<br />
DONALD T. WEED, M.D., F.A.C.S.<br />
Assistant Professor of Otolaryngology<br />
DESCRIPTION OF RESEARCH<br />
MUC4 (Sialomucin Complex) Expression in<br />
Head and Neck <strong>Cancer</strong><br />
Sialomucin complex (SMC) is a novel membrane/soluble<br />
glycoprotein complex originally<br />
identified and isolated from membranes of<br />
ascites sublines of the highly metastatic 13762 rat<br />
mammary adenocarcinoma. Peptide sequence<br />
homology between the gene product of the human<br />
mucin MUC4 and rat SMC has recently<br />
been reported. SMC is composed of a mucin subunit<br />
ASGP-1 (ascites sialoglycoprotein-1) linked<br />
to the plasma membrane via an N-glycosylated<br />
transmembrane subunit ASGP-2. The transmembrane<br />
subunit has two epidermal growth factor<br />
(EGF)-like domains and can act selectively as a<br />
ligand for the receptor tyrosine kinase ErbB2.<br />
The mucin subunit ASGP-1 also has anti-adhesive<br />
activity. The human MUC4 has corresponding<br />
transmembrane (MUC4-β) and mucin<br />
(MUC4-α) subunits, with similar growth factor<br />
domains and anti-adhesive potential. These characteristics<br />
suggest SMC/MUC4 plays a functional<br />
role in normal cells by providing a direct protective<br />
barrier at the cell surface to limit absorption<br />
of microbes and other noxious agents to the epithelial<br />
surface, while also participating in repair<br />
and cell replacement processes in the epithelia as<br />
a ligand and modulator of signaling via ErbB2.<br />
SMC/MUC4 can participate in cell signaling<br />
pathways via its complex with ErbB2 to mediate<br />
pathways characterized by cell proliferation, or<br />
pathways characterized by cell cycle inhibition<br />
and growth arrest. Disregulation of proliferative<br />
pathways may lead to transformation of the normal<br />
epithelia to a neoplastic phenotype by means<br />
of autocrine stimulation of cell growth and proliferation<br />
via activation of ErbB2. The antiadhesive<br />
properties of the ASGP-1/MUC4-α component<br />
of the molecules result in reversible disruption of<br />
integrin-mediated cell adhesion to the extracellular<br />
matrix, and may be important in the develop-<br />
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ment of metastatic potential of the transformed<br />
cell. Alternatively, SMC/MUC4 may be an important<br />
mediator of differentiation by its cell<br />
cycle inhibitory functions. MUC4 expression has<br />
been associated with several human malignancies,<br />
including some where MUC4 expression correlates<br />
with poor prognosis and others where the<br />
opposite association is seen.<br />
Immunocytochemical analyses have shown<br />
that the oral cavity is one of the earliest sites of<br />
expression of SMC during development of the<br />
rat, and that the molecule is expressed throughout<br />
the upper aerodigestive tract and in the salivary<br />
glands of the adult animal. This study<br />
postulates that human MUC4 is similarly expressed<br />
in the epithelia of the human upper aerodigestive<br />
tract and salivary glands, and that the<br />
molecule participates in the normal processes of<br />
cellular protection, repair, and replacement of<br />
these vulnerable tissues. It is further postulated<br />
that alterations in MUC4 expression are relevant<br />
to the cell biology of neoplastic transformation<br />
and subsequent invasion and metastasis of these<br />
cancers. The hypotheses of this study are threefold:<br />
1) MUC4 expression is altered in head and<br />
neck malignancies compared with normal epithelial<br />
expression; 2) cellular expression of MUC4<br />
modulates as lesions progress from dysplastic noninvasive<br />
lesions to invasive lesions with regional<br />
and distant metastases; 3) characterization of<br />
MUC4 expression in neoplasia will correlate with<br />
tumor behavior such as invasion and metastasis,<br />
and clinical outcomes such as likelihood of recurrence<br />
and prognosis.<br />
Preliminary data from immunoblotting studies<br />
using fresh frozen operative tissue samples and<br />
immunohistochemical localization studies using<br />
paraffin embedded tissue blocks have identified<br />
MUC4 throughout the normal human upper<br />
aerodigestive tract mucosa, and in major and minor<br />
salivary glands. MUC4 is identified in squamous<br />
cell carcinomas (SCCA) of the upper<br />
aerodigestive tract, as well as in metastatic cervical<br />
lymph nodes. SMC/MUC4 also is identified<br />
in a variety of salivary neoplasms. Alterations in<br />
the normal mucosal MUC4 expression are seen<br />
in otherwise histologically normal mucosa adjacent<br />
to invasive tumors. MUC4 expression in the<br />
salivary gland tumor mucoepidermoid carcinoma<br />
has been associated with improved prognosis independent<br />
of pathologic grade, the strongest<br />
known predictor of clinical behavior in this malignancy.<br />
No clear correlation between MUC4<br />
expression and ErbB2 expression was seen by immunohistochemical<br />
analysis. On the other hand,<br />
MUC4 expression was noted to be expressed in<br />
the minority (14 percent) of head and neck<br />
SCCA, but a significant association between<br />
MUC4 expression and ErbB2 expression has<br />
been identified. Furthermore, MUC4 expression<br />
is associated with improved survival and decreased<br />
risk of recurrence in these tumors as established<br />
by immunohistochemical analysis.<br />
These studies suggest that in mucoepidermoid<br />
carcinoma and in head and neck SCCA MUC4<br />
may be functioning as a marker or mediator of<br />
differentiation, with tumors that lose this expression<br />
associated with a more aggressive clinical course.<br />
These studies have established MUC4 as a<br />
novel molecular prognostic marker for these<br />
tumors. Mechanistic studies to better define the<br />
functional relationship between MUC4 and<br />
ErbB2 in these tumors are planned.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,<br />
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression<br />
of tumor markers hyaluronic acid and hyaluronidase<br />
(HYAL1) in head and neck tumors.<br />
International Journal of <strong>Cancer</strong> 106:438-45,<br />
2003.<br />
Civantos, FJ, Gomez, C, Duque, C, Pedroso, F,<br />
Goodwin, WJ, Weed, DT, Arnold, D, and<br />
Moffat, F. Sentinel node biopsy in oral cavity<br />
cancer: correlation with PET scan and immunohistochemistry.<br />
Head & Neck 25:1-9, 2003.<br />
Foster, PK and Weed, DT. Tongue viability after<br />
bilateral lingual artery ligation and surgery for<br />
recurrent tongue-base cancer. Ear, Nose, &<br />
Throat Journal 82:720-724, 2003.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
CATHERINE F. WELSH, M.D.<br />
Associate Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Welsh studies the cell cycle progression<br />
through the G1 phase and its regulation by<br />
growth factor receptors and adhesion to the extracellular<br />
matrix. Her laboratory is particularly interested<br />
in how these signaling pathways<br />
contribute to breast cancer tumorigenesis and<br />
progression. Signals from the plasma membrane<br />
emanating from receptor tyrosine kinases as well<br />
as integrins are each required for G1 progression.<br />
Cell spreading and cytoskeletal integrity as a consequence<br />
of integrin engagement also are necessary.<br />
Their laboratory studies involve the role of<br />
Rho family GTPases, a subset of the Ras superfamily,<br />
in the regulation of adhesion-dependent<br />
cell cycle progression. These proteins have been<br />
shown to play a role in integrin- and growth factor-mediated<br />
signaling, and they are potent mediators<br />
of cytoskeletal architecture during cell<br />
spreading. They are therefore situated to play a<br />
key role in the regulation of adhesion-dependent<br />
cell cycle progression. Recent research has revealed<br />
that Rho GTPases become deregulated in<br />
breast cancer and may contribute to tumorigenesis.<br />
Dr. Welsh’s laboratory is currently investigating<br />
the contribution of Rho GTPases to<br />
abnormalities in cell cycle proteins that typify<br />
poor prognosis breast cancer.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Rho family GTPases are in fact required for key<br />
adhesion-dependent G1 events, including<br />
cyclin D1 expression, Rb phosphorylation, and<br />
cyclin A expression. In addition, they participate<br />
in the activation of the mitogen-activated<br />
kinase, ERK1/2, a key upstream regulator of<br />
cyclin D1 expression. Furthermore, Rho proteins<br />
appear to be involved in determining the<br />
timing of cyclin D1 expression within G1<br />
phase.<br />
• Hyperactivation of Rho proteins in a subset of<br />
breast cancers underlies abnormalities in cell<br />
cycle regulators that typify poor prognosis<br />
breast cancer. In addition, inactivation of Rho<br />
GTPases normalizes these regulatory molecules<br />
and restores a more orderly progression through<br />
the cell cycle, even in aggressively growing<br />
breast cancer cells. Pathways mediating these<br />
actions include the MEK-ERK pathway. These<br />
findings may have implications for more targeted<br />
therapeutic approaches that specifically<br />
inhibit the autonomous proliferation of breast<br />
cancer cells.<br />
RUDOLF K. WERNER, PH.D.<br />
Professor of Biochemistry and<br />
Molecular Biology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Werner’s research focuses on the regulation<br />
of connexin43 expression. He and his colleagues<br />
had discovered that the 5’-UTR of<br />
connexin43 mRNA contains a very active internal<br />
ribosome entry site (IRES) element that appears<br />
to be regulated by estrogen. His laboratory<br />
continues to investigate this regulation in the<br />
myometrium where connexin43 is produced at<br />
parturition in response to estrogen. Dr. Werner’s<br />
research also has demonstrated that in several<br />
other tissues, such as heart and smooth muscle,<br />
connexin43 pre-mRNA is alternatively spliced<br />
producing mRNA with different 5’-UTRs but<br />
identical coding regions. This finding suggests<br />
that the expression of connexin43 is regulated at<br />
the translational level in different tissues.<br />
Dr. Werner and his colleagues discovered<br />
alternatively spliced 5’-UTR-coding exons in five<br />
other connexins. Again, the splicing seems to be<br />
tissue-specific. They currently are investigating<br />
whether some of these novel exons contain IRES<br />
elements.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
Dr. Werner’s laboratory also is pursuing the<br />
investigation of Ini, a novel transcription factor<br />
that is involved in connexin43 gene regulation at<br />
the transcriptional level. Knockout experiments<br />
in Saccharomyces pombe indicated that the yeast<br />
homolog of Ini is an essential protein. It appears<br />
to be involved in the mRNA splicing process.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Oltra, E, Pfeifer, I, and Werner, R. Ini, a small<br />
nuclear protein that enhances the response of the<br />
connexin43 gene to estrogen. Endocrinology<br />
144:3148-58, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that, in humans, connexin43 is<br />
expressed in the heart and the uterus, as well as<br />
in many other tissues. Because it is an essential<br />
protein (as determined in mice) that affects<br />
early development, it is important to understand<br />
the mechanisms of its regulation of expression.<br />
In the uterus, connexin43 expression<br />
is inducible by estrogen. This regulation is clinically<br />
important because women who suffer<br />
from premature labor also express connexins<br />
prematurely.<br />
JAMES WYCHE, PH.D.<br />
Professor of Biology<br />
DESCRIPTION OF RESEARCH<br />
One of Dr. Wyche’s interests has been to understand<br />
how anti-cancer drugs induce<br />
apoptosis (cell deaths) of cancer cells. Recently,<br />
he and his colleagues studied how the natural<br />
product camptothecin (CPT) and its semi-synthetic<br />
derivatives such as CPT-11, 9-amino-CPT<br />
(9AC), and 9-nitro-CPT (9NC) induce apoptosis<br />
of human colon cancer cells. Many aspects of the<br />
mechanism by which these drugs exert their<br />
death effect on cancer cells, however, remain<br />
largely unknown. In recent years, Dr. Wyche and<br />
his colleagues have used a cell model of human<br />
colon cancer to demonstrate that treatment with<br />
low doses of CPT induces senescence in the presence<br />
of a protein call p21. Apoptosis, however,<br />
occurs in the absence of p21. Therefore, p21 is a<br />
key determinant of the outcome of colon cancer<br />
cells treated with CPT drugs at doses that are relevant<br />
to clinical application. Thus, CPT treatment<br />
of colon cancer cells with p21 should result<br />
in disease stabilization, whereas CPT treatment<br />
of p21-deficient colon cancer cells should result<br />
in rapid apoptosis and disease regression.<br />
It is well established that p21 inhibits cyclindependent<br />
kinases (Cdks) and several other factors,<br />
including proliferating cell nuclear antigens.<br />
They hypothesize that inhibition of Cdks by p21<br />
is essential to inhibit apoptosis and induce senescence.<br />
In this context, Dr. Wyche and his colleagues<br />
propose that a protein named E2F1 is<br />
essential for apoptosis of colon cancer cells<br />
treated with CPT. According to this hypothesis,<br />
inhibition of Cdks should result in activation of<br />
another protein, named retinoblastoma (Rb),<br />
which in turn, inhibits E2F1 and consequentially<br />
E2F1-dependant apoptosis. They also hypothesize<br />
that the ability of p21 to induce senescence<br />
requires a protein called STAT1. To test their<br />
hypothesis, Dr. Wyche’s laboratory currently is<br />
using techniques to selectively alter the status of<br />
Cdk, E2F1, Rb, and STAT1 genes in human<br />
colon cancer cells. They will then investigate the<br />
role of each protein in the process of apoptosis<br />
and senescence in the colon cancer cells after<br />
CPT treatment.<br />
The information obtained from these investigations<br />
will provide a better insight into the<br />
molecular pathways activated in colon cancer<br />
cells after CPT treatment and eventually will lead<br />
to specific experimental designs to completely<br />
understand how CPTs affect colon cancer.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
SELECTED PUBLICATIONS<br />
2002<br />
Han, Z, Wei, W, Dunaway, S, Darnowski, JW,<br />
Calabresi, P, Sedivy, J, Hendrickson, EA, Balan,<br />
KV, Pantazis, P, and Wyche, JH. Role of p21 in<br />
apoptosis and senescence of human colon cancer<br />
cells treated with camptothecin. Journal of Biological<br />
Chemistry 277:17154-60, 2002.<br />
Han, Z, Ribbizi, I, Pantazis, P, Wyche, J,<br />
Darnowski, J, and Calabresi, P. The antibacterial<br />
drug taurolidine induces apoptosis by a mitochondrial<br />
cytochrome c-dependent mechanism.<br />
Anticancer Research 22:1959-64, 2002.<br />
2003<br />
Hu, X, Han, Z, Wyche, JH, and Hendrickson,<br />
EA. Helix 6 of tBid is necessary but not sufficient<br />
for mitochondrial binding activity. Apoptosis<br />
8:277-89, 2003.<br />
Pantazis, P, Han, Z, Balan, K, Wang, Y, and<br />
Wyche, JH. Camptothecin and 9-<br />
nitrocamptothecin (9NC) and anti-cancer, anti-<br />
HIV, and cell-differentiation agents:<br />
Development of resistance, enhancement of<br />
9NC-induced activities, and combination treatments<br />
in cell and animal models. Anticancer Research<br />
23:3623-38, 2003.<br />
Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche,<br />
J, Han, Z, and Pantazis, P. Differential susceptibility<br />
to 9-nitrocamptothecin (9-NC)-induced<br />
apoptosis in clones derived from a human ovarian<br />
cancer cell line: possible implications in the treatment<br />
of ovarian cancer patients with 9-NC. Anticancer<br />
Drugs 14:427-36, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• The research activities in Dr. Wyche’s laboratory<br />
focus on the use of natural products that induce<br />
the death of cancer cells. They use several human<br />
tumor types, but predominantly colon<br />
cancer cells, and exploit substances that damage<br />
the cells’ genetic material with a specific effect<br />
on killing or controlling the proliferation of<br />
theses cells. Current research has led the team<br />
to focus on key cellular proteins and manipulation<br />
of their genes that may eliminate protein<br />
production. They then observe the concomitant<br />
impact on cellular functions such as growth or<br />
death of the target cancer cell.<br />
TERESA A. ZIMMERS, PH.D.<br />
Assistant Professor of Surgery<br />
DESCRIPTION OF RESEARCH<br />
Dr. Zimmers’ research aims to understand the<br />
mechanisms regulating tissue homeostasis in<br />
order to apply such knowledge to the prevention<br />
and treatment of human disease. Recently, she<br />
has focused on the roles of the transforming<br />
growth factor-beta (TGF-ß) superfamily member—myostatin—in<br />
the regulation of skeletal<br />
muscle and fat mass. Myostatin is a highly conserved<br />
gene expressed at high levels in skeletal<br />
muscle and at low levels in white fat. Mice and<br />
cattle lacking myostatin function develop skeletal<br />
muscle hypertrophy and hyperplasia. Research<br />
in Dr. Zimmers’ laboratory has shown that<br />
overexpression of myostatin in mice produces<br />
hypoglycemia along with a wasting syndrome<br />
similar to the cachexia that complicates many<br />
chronic diseases such as cancer, AIDS, and organ<br />
failure. Concomitant over-expression of the<br />
myostatin binding proteins, follistatin and<br />
myostatin propeptide, inhibits this wasting, suggesting<br />
a means of interfering with endogenous<br />
myostatin signaling in animals and patients.<br />
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T U M O R C E L L B I O L O G Y P R O G R A M<br />
Dr. Zimmers’ current research focuses on the<br />
following questions:<br />
1) Is dysregulation of the myostatin signaling<br />
pathway involved in the etiology of muscle<br />
wasting due to cancer, AIDS, congestive heart<br />
failure, burn, or sepsis in mouse models and in<br />
humans?<br />
2) How does myostatin regulate muscle and fat<br />
mass in vivo?<br />
3) What are the target genes induced by<br />
myostatin signaling?<br />
4) How does myostatin influence glucose homeostasis?<br />
5) How does myostatin-induced wasting differ<br />
from that induced by cytokines such as<br />
interleukin-6 (IL-6) or tumor necrosis factor<br />
(TNF)?<br />
Dr. Zimmers’ latest data derived from<br />
microarray analysis of RNA from muscle cells<br />
treated in vitro and in vivo with myostatin suggest<br />
that myostatin may regulate skeletal muscle mass<br />
on several levels, including by altering proteolysis,<br />
cell proliferation and apoptosis, and cell energetics/metabolism.<br />
Using this approach, she has<br />
identified a number of candidate genes that<br />
might control skeletal muscle regulation in normal<br />
development and disease.<br />
A second, long-standing focus of Dr.<br />
Zimmers’ research is the remarkable phenomenon<br />
of liver regeneration, a striking manifestation<br />
of tissue growth regulation. The laboratory<br />
has examined the roles of several members of the<br />
TGF-ß superfamily in liver regeneration using<br />
gene targeting, transgenesis and overexpression<br />
studies. Using such strategies, they demonstrated<br />
that the TGF-ß family members inhibin-ßC and<br />
–ßE, alone and in combination, and bone morphogenetic<br />
protein (BMP)-9 are not essential for<br />
liver regeneration after hepatectomy.<br />
Dr. Zimmers’ current work, done in collaboration<br />
with Leonidas G. Koniaris, M.D., focuses<br />
upon the role of the IL-6 signaling pathway in<br />
hepatocyte proliferation. They have shown that<br />
administering high levels of IL-6 to mice results<br />
in profound liver growth (with concomitant peripheral<br />
cachexia) without activating known<br />
growth factor signaling pathways. These results<br />
suggest that IL-6 may be a hepatocyte mitogen.<br />
Because elevated IL-6 levels also are associated<br />
with human liver disease, however, their current<br />
effort focuses upon identifying the mechanisms<br />
by which IL-6 induces liver growth and facilitate<br />
regeneration when administered acutely, but suppresses<br />
the regenerative response and potentially<br />
contributes to progressive liver injury and failure<br />
when present chronically.<br />
Finally, a chance observation that mice<br />
treated with high-dose IL-6 develop increased<br />
intestinal growth (increased gut length, diameter,<br />
and mass) has led to a third project examining<br />
the role of IL-6 in epithelial cell proliferation in<br />
the gut.<br />
Dr. Zimmers’ ultimate goal is to apply what<br />
is learned in the basic science laboratory to solving<br />
clinical problems, including the treatment of<br />
patients with muscle wasting disorders, obesity,<br />
diabetes, and liver disease.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Zimmers, TA , Davies, MV, Koniaris, LG,<br />
Haynes, P, Tomkinson, KN, McPherron, AC,<br />
Wolfman, NM, and Lee, S-J. Cachexia induced<br />
by systemic myostatin administration in mice.<br />
Science 296:1486-1488, 2002.<br />
2003<br />
Sean, JJ, Klover, PJ, Nowak, IA, Zimmers, TA ,<br />
Koniaris, LG, Furlanetto, RW, and Mooney, RA.<br />
Suppressor of cytokine signaling-3, a potential<br />
mediator of interleukin-6 dependent insulin resistance<br />
in hepatocytes. Journal of Biological Chemistry<br />
278:13740-13746, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 101
T U M O R C E L L B I O L O G Y P R O G R A M<br />
Koniaris, LG, McKillop, IH, Schwartz, SI, and<br />
Zimmers, TA . Liver regeneration. Journal of the<br />
American College of Surgeons 197:634-59, 2003.<br />
Zimmers, TA , McKillop, IH, Pierce, RH, Yoo,<br />
JY, and Koniaris, LG. Massive liver growth in<br />
mice induced by systemic interleukin 6 administration.<br />
Hepatology 38:326-34, 2003.<br />
Klover, PJ, Zimmers, TA , Koniaris, LG, and<br />
Mooney, RA. Chronic exposure to interleukin-6<br />
causes hepatic insulin resistance in mice. Diabetes<br />
52:2784-89, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated that overexpression of the TGFß<br />
family member, myostatin, leads to hypoglycemia<br />
and muscle and fat wasting despite<br />
adequate food intake, suggesting a role for the<br />
myostatin pathway in the etiology or treatment<br />
of human wasting diseases such as cancer<br />
cachexia.<br />
• Observed that overexpression of the inflammatory<br />
cytokine IL-6 leads to hypoglycemia and<br />
peripheral cachexia, along with increased liver<br />
and bowel growth, suggesting a role for IL-6 in<br />
human wasting syndromes and in treatment or<br />
progression of liver disease, hepatocellular carcinomas,<br />
or short gut syndrome.<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
T U M O R I M M U N O L O G Y P R O G R A M<br />
PROGRAM LEADER<br />
Diana M. Lopez, Ph.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF PROGRAM<br />
The Tumor Immunology Program presently<br />
consists of 15 faculty members from four different<br />
departments at the University of Miami<br />
School of Medicine. The program comprises<br />
multiple aspects of basic immunology and a substantial<br />
number of studies involving tumor systems<br />
and samples obtained from patients. The<br />
program investigates numerous characteristics of<br />
the immune system in relation to the development<br />
and treatment of cancer.<br />
GOALS OF PROGRAM<br />
1) Elucidate the mechanisms underlying the activities<br />
of innate and adaptive immune cells.<br />
2) Study various aspects of stem cell biology and<br />
bone marrow transplantation.<br />
3) Analyze the role of T cells and B cells in the<br />
host defenses against tumors.<br />
4) Study the mechanisms of tumor evasion of the<br />
immune system.<br />
5) Devise novel immunotherapeutic protocols.<br />
PARTICIPANTS<br />
Adkins, Rebecca D., Ph.D.<br />
Microbiology and Immunology<br />
Blomberg, Bonnie B., Ph.D.<br />
Microbiology and Immunology<br />
Jurecic, Roland, Ph.D.<br />
Microbiology and Immunology<br />
Lee, Kelvin P., M.D.<br />
Microbiology and Immunology<br />
Levy, Robert B., Ph.D.<br />
Microbiology and Immunology<br />
Lichtenheld, Mathias G., M.D.<br />
Microbiology and Immunology<br />
Lopez, Diana M., Ph.D.<br />
Microbiology and Immunology<br />
Malek, Thomas R., Ph.D.<br />
Microbiology and Immunology<br />
Podack, Eckhard R., M.D., Ph.D.<br />
Microbiology and Immunology<br />
Riley, Richard L., Ph.D.<br />
Microbiology and Immunology<br />
Rosenblatt, Joseph D., M.D.<br />
Medicine<br />
Thomas, Giovanna R., M.D.<br />
Otolaryngology<br />
Tolba, Khaled, M.D.<br />
Medicine<br />
Torroella-Kouri, Marta, Ph.D.<br />
Microbiology and Immunology<br />
Vincek, Vladimir, M.D., Ph.D.<br />
Pathology<br />
HIGHLIGHTS<br />
• Recent findings reveal that the primary function<br />
of interleukin 2 (IL-2) is the generation of<br />
T regulatory cells and not T-cell proliferation<br />
and sensitization to cell death as previously<br />
thought. (T. Malek)<br />
• During in vitro priming, IL-2 promotes subsequent<br />
engraftment and successful adoptive tumor<br />
immunotherapy by persistent memory<br />
phenotypic CD8 + T cells. (T. Malek)<br />
• Heatshock fusion vaccines generate CD8<br />
cytotoxic T lymphocytes (CTL) without CD4<br />
help; progress towards novel and efficient tumor-specific<br />
vaccines is underway. (E. Podack)<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
• CD30 is identified as a major negative regulator<br />
of cytotoxic lymphocytes; blocking CD30 signals<br />
in vivo may enhance anti-tumor immune<br />
responses. (E. Podack)<br />
• A phase I study testing a vaccine therapy protocol<br />
in advanced non-small cell lung carcinoma<br />
showed that the vaccine was safe and stimulated<br />
an immune response. Clinical benefit was seen<br />
in six patients. (E. Podack)<br />
• A role for perforin in lymphocyte homeostasis<br />
revealed that cytotoxicity by perforin is necessary<br />
to remove antigen-presenting cells and turn<br />
off T-cell activation. (E. Podack)<br />
• A unique peptide with immunoenhancing<br />
properties has been identified in a secreted form<br />
of human MUC1 and used in vaccination experiments.<br />
This peptide inhibits tumor development<br />
in the mammary cells transfected with the<br />
secreted MUC1 and also protects against a variety<br />
of other tumor types. (D. Lopez)<br />
• Thymuses of mammary tumor bearers are profoundly<br />
involuted, and this is not due to a decrease<br />
of the thymocytes proliferation. A minor<br />
increase of apoptosis was noted; however, the<br />
major cause of this phenomenon appears to be<br />
an arrest at an early stage of differentiation, possibly<br />
brought about by the direct or indirect<br />
effects of tumor derived factors. (D. Lopez and<br />
R. Adkins)<br />
• After allogeneic bone marrow transplant, the<br />
recipient can resist the engraftment of transplanted<br />
donor stem cells by using immune responses,<br />
which do not involve the two major<br />
pathways of T lymphocyte-mediated killing.<br />
This is a surprising finding and demonstrates<br />
that it is likely that for some transplants, different<br />
pathways in the recipient must be blocked<br />
to help the transplanted bone marrow engraft.<br />
(R. Levy)<br />
• Lymphocytes, which were added to donor stem<br />
cells before transplant to help or facilitate the<br />
engraftment by these stem cells after transplant,<br />
use different functions for the purposes of: 1)<br />
helping to “seed” the stem cells in the recipient,<br />
and 2) helping to maintain their permanent<br />
presence. (R. Levy)<br />
• Direct activation of protein kinase C (PKC)<br />
causes normal human hematopoietic CD34 +<br />
stem cells to differentiate into dendritic cells<br />
(DC). (K. Lee)<br />
• PKC activation causes many myeloid leukemias<br />
to differentiate into immunologically functional<br />
“leukemic” DC. These cells have potential utility<br />
as “cellular” anti-leukemia vaccines. (K. Lee)<br />
• Researchers identified two essential enhancers<br />
of the perforin gene and demonstrated that they<br />
are under the control of Stat5 molecules. This<br />
work sheds molecular light on fundamental<br />
principles of effector gene activation in cytotoxic<br />
lymphocytes. (M. Lichtenheld)<br />
• Compromised humoral immune response in<br />
aged individuals may be at least partially explained<br />
by antibody V H<br />
repertoire differences at<br />
the pre-B cell level (before antigen selection).<br />
(B. Blomberg)<br />
• Breast cancer patients show improved immune<br />
response after psychosocial intervention. (B.<br />
Blomberg)<br />
• The molecular deficits, which underlie dysfunctions<br />
in lymphocyte activity during old age,<br />
have yet to be well characterized. The finding<br />
that expression of a transcription factor (E47)<br />
and surrogate light chains, both of which are<br />
critical to B-lineage cell development, are decreased<br />
in aged B-cell precursors provides a molecular<br />
basis for understanding deficient<br />
lymphopoiesis in senescence. (R. Riley)<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
REBECCA D. ADKINS, PH.D.<br />
Associate Professor of Microbiology and<br />
Immunology<br />
DESCRIPTION OF RESEARCH<br />
<strong>Cancer</strong> in infants and children differs markedly<br />
from that in adults. For example, there<br />
are some solid tumors that occur in children but<br />
never or rarely develop in adults, including neuroblastoma,<br />
Wilms tumor, rhabdomyosarcoma,<br />
osteosarcoma, hepatoblastoma, Ewing’s sarcoma,<br />
and retinoblastoma. Moreover, solid tumors as<br />
well as hematologic malignancies, such as acute<br />
lymphoblastic leukemia (ALL) or acute myeloid<br />
leukemia (AML), demonstrate distinct biological<br />
features and responses to treatment in children<br />
and adults. During the last half of the 20 th century,<br />
great strides were made in improving survival<br />
rates of many pediatric cancers. This was<br />
achieved largely by increasing the aggression of<br />
chemotherapy treatments. Because of the high<br />
intensity of current therapy, however, future improvements<br />
are unlikely to come from further<br />
increases in chemotherapy intensity. Moreover,<br />
chemotherapy is not ideal for use in children because<br />
of adverse side effects that can manifest in<br />
later life. In this light, it appears that the improved<br />
survival of pediatric cancer patients is<br />
awaiting the application of new therapeutic regimens.<br />
One relatively new and especially promising<br />
approach for treating cancers in adults is the<br />
application of immunotherapy. A good deal of<br />
attention is being paid to the possibility of<br />
enhancing endogenous anti-tumor responses.<br />
Because of the limitations with current therapies,<br />
the idea of enhancing the anti-tumor responses of<br />
children with cancer is very appealing. At the<br />
present time, however, all hands are tied because<br />
there simply is not enough known about the<br />
neonatal/juvenile immune system to devise the<br />
appropriate immunotherapeutic approaches.<br />
Using a mouse model system, Dr. Adkins has<br />
focused on studying the development of immune<br />
system function in neonatal life. Her laboratory<br />
has made many interesting and important<br />
observations that have significantly broadened<br />
the knowledge base of neonatal immunity. First,<br />
Dr. Adkins and her colleagues have shown that,<br />
unlike in adults, responses mediated by T lymphocytes<br />
differ in the newborn lymph nodes and<br />
spleen. Second, they have found that neonates<br />
show an abnormal persistence of anti-inflammatory<br />
T-cell responses following exposure to model<br />
vaccine antigens. Third, they have demonstrated<br />
definitively that the immature responses of neonatal<br />
T lymphocytes are due to inherent properties<br />
of this population of cells rather than<br />
immature signals in the neonatal environment.<br />
Lastly, they most recently discovered that the<br />
properties of neonatal T lymphocytes are at least<br />
partly due to an “imprinting” that occurs during<br />
embryonic life. Currently, Dr. Adkins and her<br />
colleagues are beginning to uncover the molecular<br />
regulation of the neonatal phenomenon.<br />
These studies will aim at identifying new tools that<br />
can be applied to enhancing neonatal immune<br />
responses. It is becoming increasingly apparent<br />
that murine newborns are immunologically quite<br />
similar to human fetuses and infants. On this<br />
basis, it reasonably can be argued that they stand<br />
to learn a great deal about what is potentially<br />
happening in humans by studying murine models.<br />
Thus, the long-term goal of these studies will<br />
be to utilize the information gained here to devise<br />
new strategies for the prevention and treatment<br />
of pediatric cancer.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Muller-Sieburg, CE, Cho, RH, Thoman, M,<br />
Adkins, B, and Sieburg, HB. Deterministic regulation<br />
of hematopoietic stem cell self-renewal and<br />
differentiation. Blood 100:1302-9, 2002.<br />
Adkins, B, Bu, Y, and Guevara, P. Murine neonatal<br />
CD4+ lymph node cells are highly deficient in<br />
the development of antigen-specific Th1 function<br />
in adoptive adult hosts. Journal of Immunology<br />
169:4998-5004, 2002.<br />
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Lopez, DM, Charyulu, V, and Adkins, B. Influence<br />
of breast cancer on thymic function in mice.<br />
Journal of Mammary Gland Biology and Neoplasia<br />
7:191-9, 2002.<br />
2003<br />
Petito, CK, Adkins, B, McCarthy, M, Roberts, B,<br />
and Khamis, I. CD4+ and CD8+ cells accumulate<br />
in the brains of acquired immunodeficiency<br />
syndrome patients with human immunodeficiency<br />
virus encephalitis. Journal of<br />
Neurovirology 9:36-44, 2003.<br />
Adkins, B, Williamson, T, Guevara, P, and Bu, Y.<br />
Murine neonatal lymphocytes show rapid early<br />
cell cycle entry and cell division. Journal of Immunology<br />
170:4548-56, 2003.<br />
Auais, A, Adkins, B, Napchan, G, and<br />
Piedimonte, G. Immunomodulatory effects of<br />
sensory nerves during respiratory syncytial virus<br />
infection in rats. American Journal of Physiology—Lung<br />
Cellular and Molecular Physiology<br />
285:L105-13, 2003.<br />
Adkins B, Bu Y, Vincek V, and Guevara P. The<br />
primary responses of murine neonatal lymph<br />
node CD4 + cells are Th2-skewed and are sufficient<br />
for the development of Th2-biased memory.<br />
Clinical and Developmental Immunology 10:43-<br />
51, 2003.<br />
Adkins, B. Peripheral CD4 + lymphocytes derived<br />
from fetal versus adult thymic precursors differ<br />
phenotypically and functionally. Journal of Immunology<br />
171:5157, 2003.<br />
BONNIE B. BLOMBERG, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Research in Dr. Blomberg’s laboratory focuses<br />
on two projects. One of those projects involves<br />
basic research on the molecular regulation<br />
of B lymphopoiesis in mice. Generation of B<br />
lymphocytes is important in cancer patients receiving<br />
bone marrow as well as in the normal<br />
production of the humoral (antibody) response.<br />
Aged humans and other mammals have a poorer<br />
immune response to pathogens.<br />
In collaboration with Richard L. Riley,<br />
Ph.D., in the department of Microbiology and<br />
Immunology, Dr. Blomberg has shown that aged<br />
mice, those greater than or equal to about 80<br />
percent of their full life span, have a substantial<br />
decrease in the number of precursor B lymphocytes<br />
as well as the amount of the precursor B-cell<br />
receptor (preBCR) including the surrogate light<br />
chain (SLC)y5 and VpreB. Their data indicate<br />
that this affects the antibody V H<br />
repertoire at the<br />
pre-B cell level, i.e., before antigen selection.<br />
More recent data indicate that the transcription<br />
factor, E2A, is reduced in not only precursor B<br />
cells but also in mature B cells in peripheral lymphoid<br />
organs in aging, leading to defects in Ig<br />
class switch and humoral immunity. Current<br />
studies will reveal the molecular and cellular<br />
causes of these defects in the aged humoral immune<br />
response and attempt to reverse these defects.<br />
These studies are important for cancer for<br />
two reasons: 1) the depressed immune response<br />
seen in aged humans likely contributes to increased<br />
susceptibility to cancer, and 2) bone marrow<br />
transplantation given to many types of<br />
cancer patients requires generation of mature B<br />
lymphocytes from the precursors in the bone<br />
marrow. Knowledge about the cellular and molecular<br />
requirements for B lymphopoiesis in<br />
young and aged individuals should lead to improvements<br />
in the humoral immune system of<br />
cancer patients.<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
Another project in Dr. Blomberg’s laboratory<br />
involves clinical research with breast cancer patients.<br />
In collaboration with Michael H. Antoni,<br />
Ph.D., in the department of Psychiatry and Behavioral<br />
Sciences, Charles S. Carver, Ph.D., in the<br />
department of Psychology, Sharlene Weiss, R.N.,<br />
Ph.D., in the department of Medicine, and members<br />
of the <strong>Cancer</strong> Prevention and Control Program<br />
at the University of Miami <strong>Sylvester</strong><br />
<strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong>, researchers are<br />
measuring the status of various immune parameters<br />
in patients in response to psychosocial intervention<br />
(e.g., group therapy, stress reduction).<br />
Preliminary experiments have shown that intervention<br />
patients have an improved immune response<br />
as seen by the ability of their T cells to<br />
proliferate in response to an antigen-specific receptor<br />
stimulus (anti-CD3). Current studies are<br />
measuring T, NK, and lymphokine-activated<br />
killer cells (LAK) cytotoxic function as well as<br />
potential TH1/TH2 differences by cytokine production<br />
resulting from T-cell stimulation. These<br />
studies are important to allow optimal immune<br />
response in cancer patients, which will better<br />
detect and destroy residual cancer and allow for<br />
better patient survival.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Jin, Y, Fuller, L, Carreno, M, Esquenazi, V,<br />
Blomberg, BB , Wei, YT, Ciancio, G, Burke, GW<br />
3rd, Tzakis, A, Ricordi, C, and Miller, J. Functional<br />
and phenotypic properties of peripheral T<br />
cells anergized by autologous CD3(+) depleted<br />
bone marrow cells. Human Immunology 63:567-<br />
75, 2002.<br />
Burke, GW, Ciancio, C, Blomberg, BB , Rosen,<br />
A, Suzart, K, Roth, D, Kupin, W, Esquenazi, V,<br />
and Miller, J. Randomized trial of three different<br />
immunosuppressive regimens to prevent chronic<br />
renal allograft rejection. Transplantation Proceedings<br />
34:1610-11, 2002.<br />
Ricordi, C, Tzakis, A, and Miller, J. Human bone<br />
marrow cells retrovirally transduced with the allogeneic<br />
class II gene, HLA-DR3beta, down regulate<br />
anti-allogeneic responses of autologous<br />
lymphoid cells. Human Immunology 63:S19,<br />
2002.<br />
2003<br />
Mathew, JM, Blomberg, BB, Fuller, L, Burke,<br />
GW, Ciancio, G, Kenyon, N, Ricordi, C, Tzakis,<br />
AG, Esquenazi, V, and Miller, J. A novel microcell-mediated<br />
lympholytic assay for the evaluation<br />
of regulatory cells in human alloreactive<br />
CTL responses. Journal of Immunological Methods<br />
272:67-80, 2003.<br />
Blomberg, BB , Hussini, S, Fainman, H, Mathew,<br />
JM, Hernandez, A, Carreno, M, Hnatyszyn, HJ,<br />
Garcia-Morales, R, Fuller, L, Rosen, A, Ricordi,<br />
C, Tzakis, A, Miller, J, and Esquenazi, V.<br />
Retroviral transduction of an allogeneic class II<br />
gene into human bone marrow down regulates<br />
allo-immune reactivity. Human Immunology<br />
64:S128, 2003.<br />
Hernandez, A, Lindner, I, Blomberg, BB,<br />
Hussini, S, Burger, M, Mathew, JM, Carreno, M,<br />
Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A,<br />
Lee, KP, Miller, J, and Esquenazi, V. Suppression<br />
of allogeneic T-cell proliferation through blocking<br />
of NF-κB in the differentiation process of human<br />
dendritic cells. Human Immunology 64:S128,<br />
2003.<br />
Mathew, JM, Alvarez, S, Vallone, T, Blomberg,<br />
BB, Joshua, M, and Esquenazi, V. A human-<br />
SCID-mouse-islet transplant model for the evaluation<br />
of the regulatory activity of donor bone<br />
marrow cells. Human Immunology 64:S7, 2003.<br />
Van Der Put, E, Sherwood, EM, Blomberg, BB,<br />
and Riley, RL. Aged mice exhibit distinct B cell<br />
precursor phenotypes differing in activation, proliferation,<br />
and apoptosis. Experimental Gerontology<br />
38:1137-47, 2003.<br />
Blomberg, BB , Mathew, J, Fainman, H, Hussini,<br />
S, Carreno, M, Hnatyszyn, H, Garcia-Morales,<br />
R, Fuller, L, Vallone, T, Rosen, A, Esquenazi, V,<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
Frasca, D, Nguyen, D, Van Der Put, E, Riley,<br />
RL, and Blomberg, BB. The age-related decrease<br />
in E47 DNA-binding does not depend on increased<br />
Id Inhibitory proteins in bone marrowderived<br />
B cell precursors. Frontiers in Bioscience<br />
8:A110-16, 2003.<br />
Frasca D, Nguyen D, Riley RL, and Blomberg,<br />
BB. Effects of aging on proliferation and E47<br />
transcription factor activity induced by different<br />
stimuli in murine splenic B cells. Mechanisms of<br />
Ageing and Development 124:361-69, 2003.<br />
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,<br />
BB. Decreased E12 and/or E47 transcription factor<br />
activity in the bone marrow as well as in the<br />
spleen of aged mice. Journal of Immunology<br />
170:719-26, 2003.<br />
Frasca, D, Van der Put, E, Riley, RL, and<br />
Blomberg, BB . Reduced Ig class switch in aged<br />
mice correlates with decreased E47 and activation-induced<br />
cytidine deaminase. Journal of Immunology<br />
172:2155-62, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Compromised humoral immune response in<br />
aged individuals may be at least partially explained<br />
by antibody V H<br />
repertoire differences at<br />
the pre-B cell level (before antigen selection).<br />
• Decreased transcription factor E2A is important<br />
for decreased Ig class switch and optimal humoral<br />
immunity.<br />
• Demonstrated improved immune response is<br />
shown by breast cancer patients after psychosocial<br />
intervention.<br />
ROLAND JURECIC, PH.D.<br />
Assistant Professor of Microbiology<br />
and Immunology<br />
DESCRIPTION OF RESEARCH<br />
The lifelong maintenance and regenerative capacity<br />
of the blood cell-forming (hematopoietic)<br />
system depend on self-renewal, lineage commitment,<br />
and differentiation of hematopoietic<br />
stem cells (HSC) and progenitors. HSC hold tremendous<br />
promise for the development of stem<br />
cell transplantation and cell and gene therapy<br />
protocols for treatment of various diseases. Research<br />
in Dr. Jurecic’s laboratory focuses on: 1)<br />
elucidation of genetic mechanisms that regulate<br />
self-renewal, lineage commitment, and differentiation<br />
of HSC, 2) identification and functional<br />
genetic analysis of novel genes that are involved<br />
in the leukemogenesis, and 3) developmental<br />
plasticity of HSC.<br />
Molecular Genetics of Stem Cell Self-Renewal<br />
and Maintenance<br />
Self-renewal of stem cells in diverse species and<br />
tissues suggests that evolutionarily conserved<br />
mechanisms regulate this common feature. Dr.<br />
Jurecic’s laboratory is studying the role of the evolutionarily<br />
conserved Pumilio family of RNAbinding<br />
proteins in self-renewal and maintenance<br />
of mammalian hematopoietic and neural stem<br />
cells. Gain of function experiments have shown<br />
that: 1) overexpression of mouse Pum genes leads<br />
to increased maintenance and suppression of<br />
multilineage differentiation of HSC and<br />
multipotent progenitors, and 2) Pum genes support<br />
maintenance and self-renewal of multipotent<br />
hematopoietic cells through regulation of the<br />
SCF/c-kit signaling pathway.<br />
Molecular Genetics of Hematopoietic Stem Cell<br />
Differentiation<br />
The developmental cascade from HSC to mature<br />
blood cells, defined by a series of commitment<br />
steps that gradually restrict the developmental<br />
potential of intermediate progenitor cells, is regu-<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
lated by an intricate network of genes. Through a<br />
comprehensive gene expression analysis during<br />
stem cell differentiation, Dr. Jurecic and his colleagues<br />
have identified a novel evolutionarily conserved<br />
RING finger protein FLRF (Rnf41).<br />
During blood cell development, FLRF (fetal liver<br />
ring finger) acts as an E3 ubiquitin ligase and affects<br />
proliferation and differentiation of HSC and<br />
multipotent progenitors by regulating cytokine<br />
receptor levels through ligand independent degradation.<br />
By regulating steady-state levels of<br />
cytokine receptors, FLRF could be maintaining<br />
optimal signaling for a proper cellular response<br />
(proliferation, lineage commitment, differentiation)<br />
of HSC and progenitors, while preventing<br />
oversignaling that could lead to leukemogenesis.<br />
Developmental Biology and Plasticity of<br />
Hematopoietic Stem Cells<br />
HSC may have the capacity to develop into cells<br />
of unrelated tissue(s). This discovery could have<br />
important implications for designing new stem<br />
cell transplantation and cell therapy protocols for<br />
treatment of various diseases. The aim of this<br />
project is to analyze whether HSC possess the<br />
potential for differentiation into cell types other<br />
than that of blood lineages. To study the full developmental<br />
potential of HSC, Dr. Jurecic’s laboratory<br />
has developed a new in utero stem cell<br />
transplantation assay, named blastocyst engraftment<br />
assay (BEA). BEA is based on microinjection<br />
of purified HSC into mouse preimplantation<br />
embryos (blastocysts), similar to embryonic stem<br />
(ES) cell technology. Using BEA, they have demonstrated<br />
that microinjected transgenic HSC successfully<br />
engraft fetal hematopoietic tissues (yolk<br />
sac, fetal liver). They also obtained preliminary<br />
evidence that mouse adult HSC have the capacity<br />
to develop into fetal central nervous system<br />
(CNS) and heart muscle cells. If adult HSC can<br />
indeed develop into functional cells from unrelated<br />
tissues, this would permit the possibility of<br />
using autologous HSC to treat disorders affecting<br />
various tissues.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Chen, AJ, Zhou, G, Juan, T, Colicos, SM, Cannon,<br />
JP, Cabriera-Hansen, M, Meyer, CF, Jurecic,<br />
R, Copeland, NG, Gilbert, DJ, Jenkins, NA,<br />
Fletcher, F, Tan, TH, and Belmont, JW. The dual<br />
specificity JKAP specifically activates the c-Jun<br />
N-terminal kinase pathway. Journal of Biological<br />
Chemistry 277:36592-601, 2002.<br />
Spassov, DS and Jurecic, R. Cloning and comparative<br />
sequence analysis of PUM1 and PUM2<br />
genes, human members of the Pumilio family of<br />
RNA-binding proteins. Gene 299:195-204,<br />
2002.<br />
2003<br />
Spassov, DS and Jurecic, R. Mouse Pum1 and<br />
Pum2 genes, members of the Pumilio family of<br />
RNA-binding proteins, show differential expression<br />
in fetal and adult hematopoietic stem cells<br />
and progenitors small star, filled. Blood Cells,<br />
Molecules and Diseases 30:55-69, 2003.<br />
Komatsu, M, Mammolenti, M, Jones, M,<br />
Jurecic, R, Sayers, TJ, and Levy, RB. Antigenprimed<br />
CD8+ T cells can mediate resistance, preventing<br />
allogeneic marrow engraftment in the<br />
simultaneous absence of perforin-, CD95L-,<br />
TNFR1-, and TRAIL-dependent killing. Blood<br />
101:3991-99, 2003.<br />
Spassov, DS and Jurecic, R. The PUF family of<br />
RNA-binding proteins: does evolutionarily<br />
conserved structure equal conserved function?<br />
IUBMB Life 55: 359-66, 2003.<br />
Liang, H, Chen, Q, Coles, AH, Anderson, SJ,<br />
Pihan, G, Bradley, A, Gerstein, R, Jurecic, R, and<br />
Jones, SN. Wnt5a inhibits B cell proliferation<br />
and functions as a tumor suppressor in hematopoietic<br />
tissue. <strong>Cancer</strong> Cell 4:349-60, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 109
T U M O R I M M U N O L O G Y P R O G R A M<br />
HIGHLIGHTS/DISCOVERIES<br />
• Discovered Pum genes as an evolutionarily conserved<br />
intrinsic mechanism that supports the<br />
self-renewal of HSC and multipotent progenitors<br />
by regulating the SCF/c-kit signaling pathway.<br />
• Discovered a new E3 ubiquitin ligase that affects<br />
proliferation and differentiation of HSC<br />
and multipotent progenitors by regulating<br />
steady-state cytokine receptor levels through<br />
ligand independent degradation, and that may<br />
be involved in etiology of hematological malignancies.<br />
• Found that the Wnt5a gene negatively regulates<br />
B-cell proliferation, and that inactivation of<br />
Wnt5a leads to development of myeloid leukemias<br />
and B-cell lymphomas. Discovery of the<br />
deletion of the WNT5a gene and/or loss of<br />
WNT5a expression in human primary leukemias,<br />
demonstrating for the first time that the<br />
WNT5a gene functions as a tumor suppressor<br />
(in collaboration with Stephen Jones, Ph.D.,<br />
University of Massachusetts Medical School).<br />
KELVIN P. LEE, M.D.<br />
Associate Professor of Microbiology<br />
and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Research in Dr. Lee’s laboratory focuses on<br />
the cells and the molecules that play central<br />
roles in initiating the adaptive immune response.<br />
Understanding these interactions is essential for<br />
developing effective immune-based therapies<br />
against cancer. At the cellular level, they are specifically<br />
studying the dendritic cells (DC), which<br />
are thought to be the most important professional<br />
antigen presenting cell (APC). Because<br />
DC monitor the local environment for immunologic<br />
“danger” signals and control what antigens<br />
are presented to T cells to activate them, they are<br />
positioned to regulate the initiation of immune<br />
responses. Their work has examined how DC<br />
arise from hematopoietic progenitors and their<br />
intracellular/genetic characteristics. They previously<br />
have reported that activation of the protein<br />
kinase C (PKC) intracellular signal transduction<br />
pathway in human hematopoietic CD34 + stem<br />
cells causes direct differentiation to a pure population<br />
of DC. Thus, PKC signaling specifically<br />
triggers the DC differentiation “program” in<br />
these cells. Additionally, specific isoforms of PKC<br />
appear to regulate specific aspects of DC differentiation.<br />
Ongoing studies are seeking to completely<br />
characterize the components of the PKC<br />
signaling pathway and what genetic events are<br />
triggered by this signal.<br />
From a translational standpoint, researchers<br />
in Dr. Lee’s laboratory have found that in<br />
addition to normal cells, PKC activation can<br />
drive DC differentiation in acute and chronic<br />
myeloid leukemic blasts. Because these “leukemic”<br />
DC retain the ability to activate T cells and<br />
are endogenously loaded with leukemia antigens,<br />
they can potentially be used as “cellular” antileukemia<br />
vaccines by re-infusion back into patients.<br />
This work aims to bring this approach to<br />
clinical trials.<br />
In addition to the DC studies, a clinical trial<br />
(headed by Dr. Lee) and basic laboratory research<br />
currently are looking at novel agents against multiple<br />
myeloma (MM). The NCI-sponsored phase<br />
I/II clinical trial is examining arsenic trioxide +<br />
ascorbic acid in the treatment of refractory/relapsed<br />
MM. Initial results demonstrate that this<br />
combination is effective against myeloma that is<br />
resistant to standard chemotherapy (including<br />
thalidomide) with acceptable toxicity. The laboratory<br />
component of these studies seeks to understand<br />
how arsenic kills myeloma, how ascorbic<br />
acid potentiates that killing, how myeloma cells<br />
become resistant to arsenic, and which host (i.e.,<br />
patient) factors may actually help the myeloma<br />
survive in the bone marrow.<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
SELECTED PUBLICATIONS<br />
2002<br />
Strbo, N, Yamazaki, K, Lee, KP, Rukavina, D,<br />
and Podack, ER. Heat shock fusion protein<br />
gp96-Ig mediates strong CD8 CTL expansion in<br />
vivo. American Journal of Reproductive Immunology<br />
48:220-25, 2002.<br />
Bahlis, NJ, McCafferty-Grad, J, Jordan-<br />
McMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,<br />
Eckman, J, Goodman, M, Fernandez, HF, Boise,<br />
LH, and Lee, KP. Feasibility and correlates of<br />
arsenic trioxide combined with ascorbic acid-mediated<br />
depletion of intracellular glutathione for<br />
the treatment of relapsed/refractory multiple myeloma.<br />
Clinical <strong>Cancer</strong> Research 8:3658-68,<br />
2002.<br />
Gray, Parkin K, Stephan, RP, Apilado, RG, Lill-<br />
Elghanian, DA, Lee, KP, Saha, B, and Witte, PL.<br />
Expression of CD28 by bone marrow stromal<br />
cells and its involvement in B lymphopoiesis.<br />
Journal of Immunology 169:2292-302, 2002.<br />
Baumgartner, R, Durant, P, van Gessel, Y,<br />
Chattopadhyay, S, Beswick, RL, Tadaki, DK,<br />
Lasbury, M, Lee, CH, Perrin, P, and Lee, KP. Evidence<br />
for the requirement of T cell costimulation<br />
in the pathogenesis of natural Pneumocystis<br />
carinii pulmonary infection. Microbial Pathogenesis<br />
33:193-201, 2002.<br />
2003<br />
Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and<br />
Harlan, DM. Porcine CD80: cloning, characterization,<br />
and evidence for its role in direct human<br />
T-cell activation. Xenotransplantation 10:252-58,<br />
2003.<br />
McCafferty-Grad, J, Bahlis, NJ, Krett, N,<br />
Aguilar, TM, Reis, I, Lee, KP, and Boise, LH.<br />
Arsenic trioxide utilizes caspase-dependent and<br />
caspase-independent death pathways in myeloma<br />
cells. Molecular <strong>Cancer</strong> Therapeutics 2:1155-64,<br />
2003.<br />
Hernandez, A, Lindner, I, Blomberg, BB,<br />
Hussini, S, Burger, M, Mathew, JM, Carreno, M,<br />
Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A,<br />
Lee, KP, Miller, J, and Esquenazi, V. Suppression<br />
of allogeneic T cell proliferation through blocking<br />
of NF-KB in the differentiation process of<br />
human dendritic cells. Human Immunology<br />
64:S128, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Direct activation of PKC causes normal human<br />
hematopoietic CD34 + stem cells to differentiate<br />
into DC.<br />
• PKC activation causes many myeloid leukemias<br />
to differentiate into immunologically functional<br />
“leukemic” DC. These cells have potential utility<br />
as “cellular” anti-leukemia vaccines.<br />
• Specific intracellular signaling pathways downstream<br />
of PKC activation control specific aspects<br />
of DC differentiation.<br />
• Arsenic trioxide + ascorbic acid is an effective<br />
combination in the treatment of refractory/relapsed<br />
myeloma.<br />
Lindner, I, Kharfan-Dabaja, MA, Ayala, E,<br />
Kolonias, D, Carlson, LM, Beazer-Barclay, Y,<br />
Scherf, U, Hnatyszyn, JH, and Lee, KP. Induced<br />
dendritic cell differentiation of chronic myeloid<br />
leukemia blasts is associated with down-regulation<br />
of BCR-ABL. Journal of Immunology<br />
171:1780-91, 2003.<br />
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ROBERT B. LEVY, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Researchers in Dr. Levy’s laboratory study the<br />
immunological responses following allogeneic<br />
bone marrow transplantation (BMT), which<br />
determine the success or failure of the hematopoietic<br />
graft. The primary objective of these studies<br />
is to define how different effector molecules<br />
produced by transplanted donor T cells and by<br />
barrier cells in the recipient regulate the development<br />
of graft versus host disease (GVHD) and<br />
control hematopoietic engraftment, respectively.<br />
The work concerning GVHD has focused<br />
on elucidating the role of donor-mediated cytotoxicity<br />
against recipient cells following the transplant.<br />
Their findings have demonstrated that<br />
differing pathways of cytotoxicity play different<br />
roles in the GVHD process. Granule dependent<br />
cytotoxicity dependent on perforin function is<br />
important in the development and onset of the<br />
disease. Cytotoxicity mediated by CD95L (FasL)<br />
is an important pathway in the pathogenesis<br />
occurring in the liver during GVHD and also can<br />
contribute to cutaneous GVHD. Most interestingly,<br />
even when both of these molecular pathways<br />
are absent in donor T cells (i.e., when they<br />
are “doubly cytotoxic deficient”), they remain<br />
capable of inducing many GVHD symptoms and<br />
death in recipients. Dr. Levy and his colleagues<br />
have recently found that highly purified populations<br />
of CD8 + or CD4 + T cells lacking these killing<br />
functions also induce lethal GVHD posttransplant.<br />
Researchers in this laboratory also investigate<br />
the process of engraftment following BMT. These<br />
studies examine the presence of defined donor<br />
progenitor cell populations (lineage committed<br />
and more primitive multi-lineage stem cells) and<br />
peripheral chimerism in recipients post-transplant.<br />
They are interested in understanding the<br />
mechanisms used by: 1) donor lymphoid cells for<br />
their facilitation and support of progenitor cells<br />
and engraftment after transplant, and 2) barrier<br />
cells in the host, which inhibit progenitor cells<br />
112<br />
and engraftment. Their recent findings have surprisingly<br />
demonstrated that total body irradiated<br />
BMT recipients lacking both perforin- and<br />
CD95L-dependent mechanisms maintain strong<br />
barrier function. Thus, efforts directed at diminishing<br />
the host’s ability to affect cytotoxicity<br />
through these pathways are unlikely to facilitate<br />
the engraftment process. Transplant of progenitor<br />
cells with defined cytokine receptor deficiencies<br />
will be used to further investigate the molecules<br />
involved. Recent studies also have documented<br />
that during the first month following BMT, there<br />
are two defined stages of engraftment, i.e., an<br />
early period when progenitor cells from the donor<br />
are present in the recipient followed by a later<br />
period during which time such cells may be<br />
eliminated. These findings show that cytotoxic<br />
function via perforin and FasL is not necessary to<br />
establish early progenitor presence but is required<br />
for the establishment of long-term chimerism in<br />
the recipient.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Jiang, Z, Adams, GB, Hanash, AM, Scadden,<br />
DT, and Levy, RB. The contribution of cytotoxic<br />
and noncytotoxic function by donor T-cells that<br />
support engraftment after allogeneic bone marrow<br />
transplantation. Biology of Blood and Marrow<br />
Transplantation 8:588-96, 2002.<br />
Chill, JH, Nivasch, R, Levy, RB, Albeck, S,<br />
Schreiber, G, and Anglister, J. The human interferon<br />
receptor: NMR-based modeling, mapping<br />
of the IFN-alpha 2 binding site, and observed<br />
ligand-induced tightening. Biochemistry<br />
41:3575-85, 2002.<br />
Levy, RB and Aoki, C. Alpha7 nicotinic acetylcholine<br />
receptors occur at postsynaptic densities<br />
of AMPA receptor-positive and -negative excitatory<br />
synapses in rat sensory cortex. The Journal of<br />
Neuroscience 22:5001-15, 2002.<br />
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2003<br />
Yu, A, Zhou, J, Marten, N, Bergmann, CC,<br />
Mammolenti, M, Levy, RB, and Malek, TR. Efficient<br />
induction of primary and secondary T celldependent<br />
immune responses in vivo in the<br />
absence of functional IL-2 and IL-15 receptors.<br />
Journal of Immunology 170:236-42, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• After allogeneic BMT, the recipient can resist<br />
the engraftment of transplanted donor stem<br />
cells by using immune responses, which do not<br />
involve the two major pathways of T lymphocyte-mediated<br />
killing. This is a surprising finding<br />
and demonstrates that it is likely that for<br />
some transplants, different pathways in the recipient<br />
must be blocked to help the transplanted<br />
bone marrow engraft.<br />
• Lymphocytes that are added to donor stem cells<br />
before transplant to help or facilitate the engraftment<br />
by these stem cells after transplant,<br />
use different functions for the purposes of: 1)<br />
helping to “seed” the stem cells in the recipient,<br />
and 2) helping to maintain their permanent<br />
presence.<br />
MATHIAS G. LICHTENHELD, M.D.<br />
Associate Professor of Microbiology<br />
and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Cytotoxic lymphocytes defeat tumors and virus<br />
infections. Their prevailing mechanism<br />
to kill the diseased targets requires a unique organelle—the<br />
cytotoxic granule. Perforin,<br />
granzyme A, and granzyme B constitute the<br />
prototypic killer molecules of the granule, which<br />
collaborate to induce the target to commit suicide.<br />
Researchers in Dr. Lichtenheld’s laboratory<br />
investigate which genes and transcriptional<br />
mechanisms promote the identity and function<br />
of cytotoxic lymphocytes through their endowment<br />
with cytotoxic granules. Recently, his laboratory<br />
has shown that the activation and differentiation<br />
of cytotoxic lymphocytes involves the Stat<br />
signaling pathway and epigenetic controls of the<br />
perforin gene. Interestingly, distal regulatory elements<br />
rather than proximal promoter elements<br />
are involved, suggesting long-range changes of<br />
the chromatin structure, which are under investigation<br />
along with the further characterization of<br />
the far-distal enhanceosomes that may comprise a<br />
locus control-like region. To study the hierarchy<br />
of nuclear events induced during the differentiation<br />
process, these researchers are characterizing<br />
transcription factors differentially expressed in<br />
cDNA subtractions and nuclear proteins differentially<br />
present in proteomic analyses of 2D gels.<br />
The functional analysis of the respective genes is<br />
undertaken in transgenic mice and a unique<br />
model cell line for the maturation process of cytotoxic<br />
lymphocytes in which cytokine receptor<br />
signals determine the maturation process of cytotoxic<br />
lymphocytes but not their growth and survival.<br />
Frequently, dysregulation of signaling pathways<br />
is an essential component of hematopoietic<br />
malignancies. A particular example is multiple<br />
myeloma (MM), an incurable B-cell malignancy.<br />
The goal of a new project is to develop preclinical<br />
therapies defined at the molecular level. To that<br />
end, Dr. Lichtenheld’s laboratory has shown that<br />
the farnesyl transferase inhibitor R115777,<br />
known to inhibit Ras signaling, kills MM cell<br />
lines despite Ras prenylation, implying participation<br />
of Ras-independent mechanism(s). This<br />
mechanism requires activation of caspase-9. The<br />
molecular components of this pathway and their<br />
characterization are under investigation.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Zhou, J, Zhang, J, Lichtenheld, MG, and Meadows,<br />
GG. A role for NF-kappa B activation in<br />
perforin expression of NK cells upon IL-2 receptor<br />
signaling. Journal of Immunology 169:1319-<br />
25, 2002.<br />
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2003<br />
Lu, Q, Wu, A, Ray, D, Deng, C, Attwood, J,<br />
Hanash, S, Pipkin, M, Lichtenheld, MG, and<br />
Richardson, B. DNA methylation and chromatin<br />
structure regulate T-cell perforin gene expression.<br />
Journal of Immunology 170:5124-32, 2003.<br />
Beaupre, D, Grad, J, Bahlis, N, Boise, L, and<br />
Lichtenheld, MG. Farnesyl transferase inhibitors<br />
sensitize to death receptor signals and induce<br />
apoptosis of multiple myeloma cells. Leukemia &<br />
Lymphoma 44:2123-34, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Successfully cloned mouse and human perforin<br />
genes, including the functional identification of<br />
the complete transcriptional territory.<br />
• Identified Stat5 as a central player in lymphocyte-mediated<br />
cytotoxicity.<br />
• Developed a novel method to detect regulatory<br />
domains in up to 100,000 bp restriction fragments.<br />
• Demonstrated Ras-independent, caspases 9-<br />
dependent cell death of MM by farnesylation<br />
inhibitors.<br />
DIANA M. LOPEZ, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Matrix metalloproteinase-9 (MMP-9), a matrixdegrading<br />
enzyme, is crucial in tumor<br />
invasion and metastasis and is implicated in<br />
leukocyte extravasation. Dr. Lopez and her colleagues<br />
have demonstrated that during growth of<br />
the D1-7, 12-dimethylbenzanthracene-3 mammary<br />
tumor in BALB/c mice, there is progressive<br />
up-regulation of MMP-9 in splenic T cells at<br />
both the transcriptional and translational levels.<br />
Their previous work has identified several factors<br />
produced by this tumor, including PGE2, granulocyte<br />
macrophage-colony stimulating factor<br />
(GM-CSF), and phosphatidyl serine; however,<br />
none of these agents induces increased production<br />
of MMP-9 by normal splenic T cells.<br />
Although not produced by the tumor, tumor necrosis<br />
factor-alpha (TNF-α), and interleukin-6<br />
(IL-6) are up-regulated in both macrophages and<br />
B cells in tumor-bearing mice. Exposure of normal<br />
T cells to these two cytokines, however, also<br />
fails to up-regulate MMP-9 production. Vascular<br />
endothelial growth factor (VEGF) is produced by<br />
many tumors, and it was determined that the<br />
mammary tumors used in studies express high<br />
levels of this angiogenic growth factor. Importantly,<br />
splenic T cells from tumor bearers constitutively<br />
produce increased amounts of VEGF,<br />
and treatment of normal T cells with VEGF results<br />
in up-regulated MMP-9 production. Of<br />
crucial importance is their finding that tumorinfiltrating<br />
T cells also produce high levels of<br />
VEGF and MMP-9. Studies indicate that VEGF<br />
can act directly on T lymphocytes and that elevated<br />
VEGF levels may contribute to the aberrant<br />
MMP-9 secretion by mammary tumor<br />
bearers’ T cells.<br />
Development of mammary tumors results in<br />
profound down-regulation of macrophage<br />
functions. Dr. Lopez and her colleagues have<br />
previously described that peritoneal elicited macrophages<br />
(PEMs) from mice-bearing large mammary<br />
tumors have profoundly depressed<br />
production of IL-12 and nitric oxide (NO).<br />
Analysis of the molecular events occurring during<br />
these down-regulations has revealed that the<br />
mRNA expression of both IL-12p40 and the inducible<br />
nitric oxide synthase (iNOS) appears to<br />
be diminished. An analysis of transcription factors<br />
that might be involved in such phenomena<br />
was undertaken, using electromobility shift assay<br />
(EMSA). The major transcription factors reported<br />
to be involved in the synthesis of IL-<br />
12p40 are NFκB, C/EBP, ets (PU.1), and AP-1.<br />
In the case of iNOS, NFκB is the major transcription<br />
factor reported to be involved. Recent<br />
evidence using transfection experiments with<br />
dominant negative mutants suggest that C/EBP<br />
and ATF-2 also may be involved in the regulation<br />
of the iNOS promoter. Comparative studies by<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
EMSA, using probes specific for the IL-12p40<br />
and iNOS murine promoters, revealed that in<br />
macrophages from tumor-bearing mice, the binding<br />
activities of NFκB and C/EBP are downregulated<br />
in both promoters. Their results suggest<br />
that in macrophages from tumor hosts, the<br />
NFκB and C/EBP might be functionally impaired.<br />
These two transcription factors are crucial<br />
for appropriate innate immunity functions. Pertinent<br />
studies are ongoing in Dr. Lopez’s laboratory<br />
to determine if these deficiencies in the presence<br />
of the tumor environment could be due to insufficient<br />
amounts, inadequate levels of phosphorylation,<br />
or impaired translocation of these<br />
transcription factors.<br />
Implantation of DA-3 mammary tumor<br />
cells into BALB/c mice results in tumor growth,<br />
metastatic lesions, and death. These cells were<br />
transfected with genes encoding for either<br />
the transmembrane (DA-3/TM) or secreted<br />
(DA-3/sec) form of human mucin 1 (MUC1).<br />
Although the gene for the secreted form lacks the<br />
transmembrane and cytoplasmic domains, the 5’<br />
sequences of these mucins are identical. However,<br />
the gene for the secreted mucin isoform ends<br />
with a sequence encoding for a unique 11 amino<br />
acid peptide. The DA-3/TM cells or DA-3 cells<br />
transfected with the neomycin vector only (DA-<br />
3/neo) have the same in vivo growth characteristics<br />
as the parent cell line. In contrast, DA-3/sec<br />
cells implanted in nude mice resulted in tumor<br />
development verifying the tumorigenic potential<br />
of these cells. Pre-exposure of BALB/c mice to<br />
DA-3/sec cells afforded protection against challenge<br />
with DA-3/TM or DA-3/neo mammary<br />
tumors and the unrelated tumors K7, an osteosarcoma,<br />
and RENCA, a renal cell carcinoma.<br />
Partial protection against subsequent tumor<br />
challenges was also achieved by substituting<br />
the 11 amino acid peptide found only in the<br />
secreted mucin-1 isoform, as it also retarded the<br />
growth of Lewis lung carcinoma cells in C57<br />
BL/6 mice. These findings reveal that a unique<br />
peptide present in the secreted MUC1 has<br />
immunoenhancing properties and may be a<br />
potential agent for use in immunotherapy.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Sun, QL, Charyulu, V, Lobo, D, and Lopez,<br />
DM. Role of thymic stromal cell dysfunction in<br />
the thymic involution of mammary tumor-bearing<br />
mice. Anticancer Research 22:91-6, 2002.<br />
Lopez, DM, Charyulu, V, and Adkins, B. Influence<br />
of breast cancer on thymic function in mice.<br />
Journal of Mammary Gland Biology and Neoplasia<br />
7:191-99, 2002.<br />
2003<br />
Torroella-Kouri, M, Keith, JC, Ivanova, M, and<br />
Lopez, DM. IL-11-induced reduction of C/EBP<br />
transcription factor binding may contribute to<br />
the IL-12 downregulation in tumor-bearing mice.<br />
International Journal of Oncology 22:439-48,<br />
2003.<br />
Owen, JL, Iragavarapu-Charyulu, V, Gunja-<br />
Smith, Z, Herbert, LM, Grosso, JF, and Lopez,<br />
DM. Up-regulation of matrix metalloproteinase-<br />
9 in T lymphocytes of mammary tumor bearers:<br />
role of vascular endothelial growth factor. Journal<br />
of Immunology 171(8):4340-51, 2003.<br />
Torroella-Kouri, M and Lopez, D. Mammary<br />
tumor derived TGF-β impairs crucial innate immune<br />
responses in tumor hosts. Journal of Immunology<br />
and Immunopathology 5:31-38, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• The thymus is crucial for the development of<br />
T lymphocytes involved in cell-mediated immunity<br />
to tumors. The thymuses of mammary<br />
tumor bearers are profoundly involuted and<br />
their studies have shown that this is not due to<br />
a decrease of the thymocytes proliferation. A<br />
minor increase of apoptosis was noted; however,<br />
the major cause of this phenomenon appears to<br />
be an arrest at an early stage of differentiation<br />
possibly brought about by the direct or indirect<br />
effects of tumor derived factors.<br />
• A unique peptide with immunoenhancing<br />
properties has been identified in a secreted form<br />
of human MUC1 and used in vaccination ex-<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
periments. This peptide inhibits tumor development<br />
not only in the mammary cells transfected<br />
with the secreted MUC1, but also provides protection<br />
against a variety of other tumor types.<br />
• The very important molecule MMP-9 has been<br />
shown to be overproduced by T lymphocytes from<br />
tumor bearing mice due in part to the overexpression<br />
of vascular endothelial growth factor.<br />
The intriguing possibility that this molecule<br />
may be helping tumor spread is being evaluated.<br />
THOMAS R. MALEK, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
The development of lymphocytes and the<br />
regulation of the immune response are critically<br />
controlled by cytokines that mediate their<br />
function by binding to specific multi-subunit cell<br />
surface receptors. Recent evidence by others has<br />
established that the genetically inherited X-linked<br />
severe combined immunodeficiency disease<br />
(SCID) is the result of mutations in the γc cytokine<br />
receptor subunit that is a shared component of<br />
the receptors for interleukin-2 (IL-2), IL-4, IL-7,<br />
IL-9, and IL-15. This genetic defect prevents the<br />
function of these five cytokines, resulting in a<br />
severe blockade in T-lymphocyte development<br />
and a greatly impaired immune system. These<br />
cytokines and receptors are also important regulators<br />
of the peripheral immune compartment.<br />
A long-term goal of Dr. Malek’s laboratory<br />
is to understand the role of cytokine receptors,<br />
especially the IL-2 receptor, in the regulation of<br />
the immune system. A current research emphasis<br />
is to establish the molecular basis by which the γc<br />
subunit contributes to binding multiple cytokines<br />
as a component of five cytokine receptors and to<br />
determine the mechanism by which γc utilizing<br />
cytokines control T-cell development and function.<br />
Another major aim of his laboratory is to<br />
study the interaction of tumor-specific T cells<br />
with its cognate tumor to define the mechanisms<br />
responsible for failed anti-tumor immunity and<br />
to develop new strategies to more effectively engage<br />
the immune system to reject tumors.<br />
Related to these goals, progress has been<br />
made in the following areas: 1) distinct functional<br />
regions of the extracytoplasmic domain of<br />
γc have been defined and demonstrate that IL-2<br />
and IL-7 utilize largely overlapping sites within<br />
γc; 2) a cytoplasmic subdomain of γc was identified<br />
that is critical for rapid IL-2-induced receptor-mediated<br />
endocytosis, which occurs by a<br />
novel proteasome dependent pathway; 3) IL-7<br />
and IL-15 were found to be the essential gc-dependent<br />
cytokines important for thymic-dependent<br />
T-cell development, while IL-2, IL-7, and<br />
IL-15 are required for the full production of<br />
intraepithelial T lymphocytes, a second anatomical<br />
site of T-cell development; 4) separate cytoplasmic<br />
domains of the IL-7Rα chain controlled<br />
distinct activities during T-cell development,<br />
while normal IL-7R-dependent thymic development<br />
requires the integrated activity of all these<br />
domains; 5) a novel and unexpected role for IL-2<br />
in thymic development was uncovered that is essential<br />
to prevent autoimmunity and is related to<br />
the production of T regulatory cells; and 6) one<br />
important reason for failed anti-tumor immunity<br />
is that tumor-specific T cells are ignorant of the<br />
growing tumor. Memory T cells, however, were<br />
shown not to be ignorant and induced effective<br />
anti-tumor immune responses. Importantly, a<br />
dendritic cell (DC)-based vaccine potently functioned<br />
to induce tumor immunity, which sometimes<br />
may lead to the rejection of the tumor.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Olosz, F and Malek, TR. Structural basis for<br />
binding multiple ligands by the common<br />
cytokine receptor gamma-chain. Journal of Biological<br />
Chemistry 277:12047-52, 2002.<br />
Demirci, G, Gao, W, Zheng, XX, Malek, TR,<br />
Strom, TB, and Li, XC. On CD28/CD40 ligand<br />
costimulation, common gamma-chain signals,<br />
and the alloimmune response. Journal of Immunology<br />
168:4382-90, 2002.<br />
116<br />
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Malek, TR, Yu, A, Vincek, V, Scibelli, P, and<br />
Kong, L. CD4 regulatory T cells prevent lethal<br />
autoimmunity in IL-2Rbeta-deficient mice. Implications<br />
for the nonredundant function of IL-2.<br />
Immunity 17:167-78, 2002.<br />
Malek, TR. T helper cells, IL-2 and the generation<br />
of cytotoxic T-cell responses. Trends in Immunology<br />
23:465-67, 2002.<br />
2003<br />
Molano, RD, Pileggi, A, Berney, T, Poggioli, R,<br />
Zahr, E, Oliver, R, Malek, TR, Ricordi, C, and<br />
Inverardi, L. Long-term islet allograft survival in<br />
nonobese diabetic mice treated with tacrolimus,<br />
rapamycin, and anti-interleukin-2 antibody.<br />
Transplantation 75:1812-19, 2003.<br />
Bathe, OF, Dalyot-Herman, N, and Malek, TR.<br />
Therapeutic limitations in tumor-specific CD8+<br />
memory T cell engraftment. BMC <strong>Cancer</strong> 3:21,<br />
2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Established that the essential non-redundant<br />
function of IL-2 is the development of<br />
CD4 + CD25 + T regulatory cells.<br />
ECKHARD R. PODACK, M.D., PH.D.<br />
Professor and Chairman of Microbiology<br />
and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Induction of Immunity by Heat Shock<br />
Protein gp96-Ig<br />
Heat shock protein gp96 is a natural adjuvant<br />
and a peptide chaperone binding to antigen<br />
presenting cells (APC) inducing APC activation,<br />
maturation, and channeling gp96-associated<br />
peptides into the class I major histocompatibility<br />
complex (MHC) presentation pathway for<br />
priming CD8 cytotoxic T lymphocyte (CTL)<br />
responses. Gp96 is unique in that it provides<br />
antigenicity and peptide-specificity through its<br />
peptide chaperone function and adjuvanticity<br />
through its ability to bind to scavenging receptors<br />
and toll-like receptors (TLRs) and to activate<br />
APC. Realizing the potential of gp96 as a vaccine,<br />
Dr. Podack’s laboratory had previously created a<br />
gp96-Ig fusion protein that is secreted from tumor<br />
cells upon transfection. In murine studies,<br />
tumor secreted gp96-Ig induced specific CD8<br />
cytotoxic T lymphocyte (CTL) expansion and,<br />
when used as vaccine, mediated tumor rejection<br />
and long lasting tumor immunity by CD8 cells<br />
with the help of natural killer (NK) cells. Murine<br />
preclinical data suggest that human tumor cells<br />
secreting gp96-Ig will be a powerful, therapeutic<br />
CD8 CTL vaccine, because gp96-Ig provides<br />
both the adjuvant effect and the specific peptides<br />
for dendritic cell (DC) activation and presentation.<br />
Tumor secreted gp96-Ig recruits and activates<br />
DC and NK cells, and causes CD8 CTL<br />
expansion. The molecular determinants of the<br />
three-way cell interaction are studied by Dr.<br />
Podack and his colleagues. The potential of gp96-<br />
Ig to break immune tolerance to tumors is also<br />
under investigation.<br />
Death Receptor and its Ligand TL1a Mediate<br />
TH2 Switch and Contribute to Asthma<br />
The biological function of death receptor 3<br />
(DR3, TNFR-SF12) is not known. DR3-<br />
transgenes expressed on T cells were used to determine<br />
the physiological function of DR3, a<br />
member of the tumor necrosis factor (TNF)-<br />
receptor family expressing an intracellular death<br />
domain. The full-length form of DR3, a dominant<br />
negative form of DR3 (DR3-DN) lacking<br />
the intracellular death domain and an alternatively<br />
spliced form of DR3 (DR3-∆5, 6) lacking<br />
exon 5 and 6 encoding the fourth extracellular<br />
cysteine rich domain, was analyzed by Dr.<br />
Podack’s laboratory. Transgenic expression of<br />
DR3 on T cells mediated TH2 polarization of<br />
cytokine and antibody production upon T-cell<br />
activation and antigen exposure. In addition,<br />
DR3 partially inhibited T-cell receptor (TCR)<br />
driven proliferation of CD4 and CD8 cells and<br />
reduced total T cell numbers in lymphoid organs<br />
without inducing apoptosis. CD8 cells were more<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
affected by DR3 than CD4 cells. They concluded<br />
that DR3 signals may be important in effector<br />
responses to pathogens by shaping the ensuing<br />
polarization toward TH2 or toward a mixed<br />
TH1/TH2 response.<br />
DR3 transgenic mice were highly susceptible<br />
to antigen-induced airway hyper-reactivity in an<br />
asthma model in mice and produced increased<br />
quantities of interleukin-13 (IL-13) and eosinophils<br />
in the lung upon antigen exposure by inhalation.<br />
Transgenic mice expressing a dominant<br />
negative form of DR3 showed increased resistance<br />
to airway hyper reactivity when compared<br />
to wild type mice. Similarly, a blocking anti-<br />
TL1a antibody was able to ameliorate asthma in<br />
wild type mice, indicating that DR3 and TL1a<br />
are involved in the pathogenesis of asthma.<br />
CD30—Governor of T Cells?<br />
CD30-L knock-out mice, when challenged with<br />
tumor secreted gp9-Ig, exhibit severely diminished<br />
CD8 CTL expansion. When used as allogeneic<br />
bone marrow graft recipients, collaboration<br />
with the laboratory of Robert B. Levy, Ph.D.,<br />
showed that CD30-L knock-out exhibit diminished<br />
graft versus host disease in a MHC II mismatch.<br />
CD30 is highly expressed on CD45-RO<br />
memory cells and serves as a T-cell costimulator<br />
and as a regulator of trafficking molecules and of<br />
pro- and anti-apoptotic molecules. CD30 signals<br />
lead to IL-13 and Ifn-g production. Researchers<br />
in Dr. Podack’s laboratory are studying the function<br />
of CD30 and its ligand in tumor rejection<br />
following vaccination.<br />
Immunotherapy for Advanced Non-Small Cell<br />
Lung Carcinoma<br />
To determine whether CD8-mediated immune<br />
responses could be elicited in stage IIIB/IV nonsmall<br />
cell lung carcinoma (NSCLC) patients, 19<br />
subjects were immunized several times with allogeneic<br />
NSCLC cells transfected with CD80<br />
(B7.1) and HLA-A1 or A2. Patients enrolled<br />
were matched or unmatched at the HLA A1 or<br />
A2 locus and their immune response compared.<br />
Immunization significantly increased the frequencies<br />
of interferon-γ secreting CD8 T cells in<br />
all but one patient in response to ex vivo challenge<br />
with NSCLC cells. The CD8 response of<br />
matched and unmatched patients was not statistically<br />
different. NSCLC reactive CD8 cells did<br />
not react to K562. Clinically, 6 of 19 patients<br />
responded to immunization with stable disease or<br />
partial tumor regression. The study demonstrates<br />
that CD8 Ifn-γ responses against non-immunogenic<br />
or immunosuppressive tumors can be<br />
evoked by cellular vaccines even at advanced<br />
stages of disease. The positive clinical outcome<br />
suggests that non-immunogenic tumors may be<br />
highly susceptible to immune effector cells generated<br />
by immunization. Further trials with curative<br />
intent are warranted.<br />
Macrophage-Perforin, a New Member of the<br />
Perforin/C9 Family of Proteins<br />
Searching the genomic database with perforin as<br />
query sequence, Dr. Podack and colleagues found<br />
two novel members of the perforin family. Structure<br />
analysis suggests that the novel members<br />
have a typical pore-forming domain but that the<br />
proteins themselves are membrane anchored. Expressed<br />
sequence tags (EST) analysis suggests that<br />
one new perforin member is expressed in trophoblast<br />
cells, while the second member is expressed<br />
in macrophages. The laboratory has cloned the<br />
macrophage-perforin (MΦ-Pf) and fused a gfp<br />
tag to it for ease of detection. Expression of MΦ-<br />
Pf-gfp in NIH 3T3 cells and in 293T cells results<br />
in fluorescence in the nucleus and in the cytoplasm.<br />
Fluorescent cells, however, subsequently<br />
round up and die, and after several days no fluorescence<br />
is detected. The data suggest that expression<br />
of MΦ-Pf leads to cell death, putatively by<br />
ectopic expression of a pore former. The data further<br />
suggest that MΦ-perforin and trophoblastperforin<br />
have essential lytic functions that need to<br />
be carefully regulated for expression. Dr. Podack’s<br />
laboratory team is in the process of deleting MΦ-<br />
Pf and trophoblast-Pf in order to discover their<br />
physiological function.<br />
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SELECTED PUBLICATIONS<br />
2002<br />
Metkar, SS, Wang, B, Aguilar-Santelises, M, Raja,<br />
SM, Uhlin-Hansen, L, Podack, ER, Trapani, JA,<br />
and Froelich, CJ. Cytotoxic cell granule-mediated<br />
apoptosis: perforin delivers granzyme B-serglycin<br />
complexes into target cells without plasma membrane<br />
pore formation. Immunity 16:417-28,<br />
2002.<br />
Kawasaki, C, Ohshima, K, Muta, H, Muta, K,<br />
Deyev, V, Podack, ER, and Kikuchi, M. Prognostic<br />
value of Bcl 10 rearrangement in diffuse large<br />
B-cell lymphoma. Leukemia & Lymphoma<br />
43:823-26, 2002.<br />
Merger, M, Viney, JL, Borojevic, R, Steele-<br />
Norwood, D, Zhou, P, Clark, DA, Riddell, R,<br />
Maric, R, Podack, ER, and Croitoru, K. Defining<br />
the roles of perforin, Fas/FasL, and tumour<br />
necrosis factor alpha in T cell induced mucosal<br />
damage in the mouse intestine. Gut 51:155-63,<br />
2002.<br />
Harlin, H, Podack, ER, Boothby, M, and Alegre,<br />
ML. TCR-independent CD30 signaling selectively<br />
induces IL-13 production via a TNF receptor-associated<br />
factor/p38 mitogen-activated<br />
protein kinase-dependent mechanism. Journal of<br />
Immunology 169:2451-59, 2002.<br />
Nam, SY, Cho, KS, Heo, YM, Ha, JC, Kim, YH,<br />
Keun Yi, H, Han Hwang, P, Kim, HM, and<br />
Podack, ER. Regulation of lymphocyte clustering<br />
by CD30-mediated ICAM-1 up-regulation. Cellular<br />
Immunology 219:38-47, 2002.<br />
Laskarin, G, Tokmadzic, VS, Strbo, N, Bogovic,<br />
T, Szekeres-Bartho, J, Randic, L, Podack, ER,<br />
and Rukavina, D. Progesterone induced blocking<br />
factor (PIBF) mediates progesterone induced suppression<br />
of decidual lymphocyte cytotoxicity.<br />
American Journal of Reproductive Immunology<br />
48:201-9, 2002.<br />
Par, G, Rukavina, D, Podack, ER, Horanyi, M,<br />
Szekeres-Bartho, J, Hegedus, G, Paal, M,<br />
Szereday, L, Mozsik, G, and Par, A. Decrease in<br />
CD3-negative-CD8dim(+) and Vdelta2/<br />
Vgamma9 TcR+ peripheral blood lymphocyte<br />
counts, low perforin expression and the impairment<br />
of natural killer cell activity is associated<br />
with chronic hepatitis C virus infection. Journal<br />
of Hepatology 37:514, 2002.<br />
Strbo, N, Yamazaki, K, Lee, K, Rukavina, D, and<br />
Podack, ER. Heat shock fusion protein gp96-Ig<br />
mediates strong CD8 CTL expansion in vivo.<br />
American Journal of Reproductive Immunology<br />
48:220-25, 2002.<br />
Tokmadzic, VS, Tsuji, Y, Bogovic, T, Laskarin, G,<br />
Cupurdija, K, Strbo, N, Koyama, K, Okamura,<br />
H, Podack, ER, and Rukavina, D. IL-18 is<br />
present at the maternal-fetal interface and enhances<br />
cytotoxic activity of decidual lymphocytes.<br />
American Journal of Reproductive Immunology<br />
48:191-200, 2002.<br />
Podack, ER, Strbo, N, Sotosec, V, and Muta, H.<br />
CD30-governor of memory T cells? Annals of the<br />
New York Academy of Sciences 975:101-13,<br />
2002.<br />
2003<br />
Dai, J, Liu, B, Caudill, MM, Zheng, H, Qiao, Y,<br />
Podack, ER, and Li, Z. Cell surface expression of<br />
heat shock protein gp96 enhances cross-presentation<br />
of cellular antigens and the generation of<br />
tumor-specific T cell memory. <strong>Cancer</strong> Immunity<br />
3:1, 2003.<br />
Dix, RD, Podack, ER, and Cousins, SW. Loss of<br />
the perforin cytotoxic pathway predisposes mice<br />
to experimental cytomegalovirus retinitis. Journal<br />
of Virology 77:3402-8, 2003.<br />
Strbo, N, Oizumi, S, Sotosek-Tokmadzic, V, and<br />
Podack, ER. Perforin is required for innate and<br />
adaptive immunity induced by heat shock protein<br />
gp96. Immunity 18:381-90, 2003.<br />
Gulan, G, Ravlic-Gulan, J, Strbo, N, Sotosek, V,<br />
Nemec, B, Matovinovic, D, Rubinic, D, Podack,<br />
ER, and Rukavina, D. Systemic and local expression<br />
of perforin in lymphocyte subsets in acute<br />
and chronic rheumatoid arthritis. Journal of<br />
Rheumatology 30:660-70, 2003.<br />
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Dix, RD, Podack, ER, and Cousins, SW. Murine<br />
cytomegalovirus retinitis during retrovirus-induced<br />
immunodeficiency (MAIDS) in mice:<br />
interleukin-2 immunotherapy correlates with increased<br />
intraocular levels of perforin mRNA. Antiviral<br />
Research 59:111-19, 2003.<br />
Raez, L, Cassileth, PA, Schlesselman, JJ,<br />
Padmanabhan, S, Fisher, EZ, Baldie, PA,<br />
Sridhar, K, and Podack, ER. Induction of CD8<br />
T-cell-Ifn-γ response and positive clinical outcome<br />
after immunization with gene-modified<br />
allogeneic tumor cells in advanced non-small-cell<br />
lung carcinoma. <strong>Cancer</strong> Gene Therapy 10:850-<br />
58, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Completed successful lung tumor vaccine trial.<br />
• Discovered that MΦ-perforin, a new member<br />
of the perforin family, promises interesting discoveries.<br />
• Discovered that death receptor 3 does not kill,<br />
but produces, IL-13, which is immunosuppressive<br />
and mediates asthma.<br />
• Realized potential of heat shock proteins to<br />
enter the clinical field of immunotherapy.<br />
RICHARD L. RILEY, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Altered B Cell Development in Senescence<br />
Senescent mice show diminished B lymphopoiesis<br />
when compared to young mice and typically<br />
exhibit decreased numbers of pre-B cells and<br />
newly formed B cells within the bone marrow.<br />
Researchers in Dr. Riley’s laboratory have focused<br />
upon elucidating the mechanisms responsible for<br />
the altered B lymphopoiesis in old age and the<br />
ramifications for antibody repertoire and humoral<br />
immunity. In particular, he and his colleagues<br />
have found that B lymphopoiesis in old<br />
age is partially interrupted at the pro-B to pre-B<br />
cell transition, a developmental step that requires<br />
both function of the pre-B cell receptor complex<br />
and responses to the growth and survival cytokine<br />
interleukin-7 (IL-7). Expression of a critical component<br />
of the pre-B cell receptor, the surrogate<br />
light chain, is reduced in aged mice, and IL-7<br />
responsiveness is diminished. This predisposes the<br />
B-cell precursors in aged mice to apoptotic cell<br />
death. These functions, and others important to<br />
B-cell development, are governed, in part, via the<br />
transcriptional regulator E2A. E2A expression<br />
also is compromised in old age; this appears to<br />
involve enhanced degradation of E2A proteins.<br />
As a consequence of the B-cell developmental<br />
deficits in old age, the repertoire of antibody<br />
specificities is skewed and the capacity to develop<br />
effective immune responses is hindered.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Riley, RL, Knowles, J, and King, AM. Levels of<br />
E2A protein expression in B cell precursors are<br />
stage-dependent and inhibited by stem cell factor<br />
(c-kit ligand). Experimental Hematology<br />
30:1412-18, 2002.<br />
2003<br />
Van Der Put, E, Sherwood, EM, Blomberg, BB,<br />
and Riley, RL. Aged mice exhibit distinct B cell<br />
precursor phenotypes differing in activation, proliferation<br />
and apoptosis. Experimental Gerontology<br />
38:1137-47, 2003.<br />
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,<br />
BB. Decreased E12 and/or E47 transcription factor<br />
activity in the bone marrow as well as in the<br />
spleen of aged mice. Journal of Immunology<br />
170:719-26, 2003.<br />
Sherwood, EM, Xu, W, and Riley, RL. B cell precursors<br />
in senescent mice exhibit decreased recruitment<br />
into proliferative compartments and<br />
altered expression of Bcl-2 family members.<br />
Mechanisms of Ageing and Development<br />
124:147-53, 2003.<br />
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Frasca, D, Nguyen, D, Riley, RL, and Blomberg,<br />
BB. Effects of aging on proliferation and E47<br />
transcription factor activity induced by different<br />
stimuli in murine splenic B cells. Mechanisms of<br />
Ageing and Development 124:361-69, 2003.<br />
Frasca, D, Nguyen, D, Van Der Put, E, Riley,<br />
RL, and Blomberg, BB. The age-related decrease<br />
in E47 DNA-binding does not depend on increased<br />
Id Inhibitory proteins in bone marrowderived<br />
B cell precursors. Frontiers in Bioscience<br />
8:A110-6, 2003.<br />
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,<br />
BB. Decreased E12 and/or E47 transcription factor<br />
activity in the bone marrow as well as in the<br />
spleen of aged mice. Journal of Immunology<br />
170:719-26, 2003.<br />
Wilson, EL, Sherwood, EM, King, AM, and<br />
Riley, RL. A phenotypically distinct subset of<br />
bone marrow immature B cells exhibits partial<br />
activation, increased survival, and preferential<br />
expression of VhS107. European Journal of Immunology<br />
33:3398, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Molecular deficits, which underlie dysfunctions<br />
in lymphocyte activity during old age, have yet<br />
to be well characterized. These findings, that<br />
expression of a transcription factor (E2A) and<br />
surrogate light chains, both of which are critical<br />
to B-lineage cell development, are decreased in<br />
aged B-cell precursors, provide a molecular basis<br />
for understanding deficient lymphopoiesis in<br />
senescence.<br />
JOSEPH D. ROSENBLATT, M.D.<br />
Professor of Medicine and<br />
Division Chief of Hematology-Oncology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Rosenblatt’s research focuses on the development<br />
of novel immune therapy and gene<br />
therapy strategies for cancer. Current research has<br />
focused on the potential role of recruitment of<br />
immune effector cells, using the local elaboration<br />
of both constitutive and inflammatory chemokines,<br />
such as secondary lymphoid chemokine<br />
(SLC), DC-CK1, and/or RANTES respectively,<br />
on the development of an anti-tumor response.<br />
Chemokine delivery has been investigated alone,<br />
or in combination with, expression of the costimulatory<br />
ligands CD80 (B7.1) or CD40L.<br />
Several delivery strategies have been investigated<br />
including the use of retroviral vectors, and/or the<br />
use of herpes simplex virus (HSV) amplicon vectors<br />
in several murine tumor models. Preliminary<br />
results suggest that the recruitment of naïve T<br />
cells using SLC is a particularly effective means of<br />
enhancing the anti-tumor immune response, particularly<br />
when combined with CD40L-induced<br />
co-stimulation. This strategy is being formally<br />
investigated using the OT-1 transgenic mouse<br />
model, which has a constitutively expressed T-cell<br />
receptor with defined anti-ovalbumin specificity<br />
and the murine tumors expressing the target ovalbumin<br />
antigen, for effects on tumor-induced tolerance<br />
and the development of systemic<br />
immunity.<br />
In a separate effort, the utility of HSV-derived<br />
helper virus-free amplicons is being tested<br />
for efficacy in augmenting the immunogenicity<br />
and antigen-presenting capability of fresh chronic<br />
lymphocytic leukemia cells (CLL). Both CD40L,<br />
CD80, and/or the tumor necrosis factor (TNF)<br />
ligand family member LIGHT, have been targeted<br />
to fresh CLL cells using the helper free<br />
HSV amplicons. Results suggest the augmented<br />
ability of such CLL cells to present antigen in an<br />
allogeneic mixed-lymphocyte-tumor cell reaction<br />
and/or to serve as stimulatory cells for the deriva-<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
tion of autologous cytolytic T cells in vitro without<br />
deleterious effects on major histocompatibility<br />
complex (MHC)-I expression seen with HSV<br />
helper virus-containing preparations.<br />
A novel means of immune effector molecule<br />
delivery, which combines the antigen binding<br />
capabilities and localization characteristics of antibodies<br />
with the local delivery of a co-stimulatory<br />
molecule, anti-angiogenic peptide, or a<br />
chemokine, also is under investigation. Antibody<br />
fusion proteins targeting the human breast and<br />
ovarian cancer her2/neu antigen, linked to the<br />
extracellular domains of the B7.1 and/or 41BB-L<br />
costimulatory ligands, have been synthesized and<br />
the in vitro ability to bind to cognate antigenic<br />
targets and to deliver a local costimulatory signal<br />
documented. Additional fusions currently being<br />
developed in the laboratory include fusion of the<br />
anti-angiogenic peptide endostatin to anti-her2/<br />
neu antibody sequences, as well as fusion of the<br />
inflammatory chemokine RANTES. Selective<br />
targeting of immune effector cells using both local<br />
chemokine vector administration or antibodyfusion<br />
protein administration is being evaluated<br />
further.<br />
A novel antibody-fusion that targets delivery<br />
of endostatin to the site of her2/neu expressing<br />
tumors also has been synthesized in collaboration<br />
with Seung-Uon Shin, M.D., and shows excellent<br />
efficacy in preclinical models. This fusion appears<br />
to substantially improve the results obtained with<br />
either antibody or endostatin alone.<br />
Currently, Dr. Rosenblatt’s laboratory is<br />
studying efficacy using a novel B-cell deficient<br />
mouse model, which allows testing of antibody<br />
fusion protein targeting to xenogeneic (e.g., CEA,<br />
her2/neu) antigens, while preserving T-cell immune<br />
effector functions. The B cell-deficient model<br />
also has demonstrated that T-cell responses to<br />
tumor may be better than those seen in the immunocompetent<br />
mouse. The laboratory currently<br />
is investigating the reasons for altered responses<br />
in the absence of B cells and the possibility of<br />
applying this approach to the human setting using<br />
antibody depletion of B cells with rituximab.<br />
Dr. Rosenblatt and his colleagues also have<br />
collaborated with the laboratory of Vicente<br />
122<br />
Planelles, Ph.D., at the University of Utah, on<br />
the development of several new approaches to<br />
HIV-1 gene therapy. These include the use of<br />
mutated tRNA LYS3 primers, which can anneal to<br />
the sequences other than primer–binding sequences<br />
on the HIV-1 genome, or tRNA LYS3 mutated<br />
in adenosine residue A58, which prevents<br />
normal methylation of the adenosine residue and<br />
disrupts proper termination of the nascent reverse<br />
transcript, thereby inhibiting completion of HIV-<br />
1 reverse transcription in model systems. Other<br />
investigations have centered on the effects of defective<br />
HIV-1 derived vectors on HIV-1 spread in<br />
culture. Recent experiments have demonstrated<br />
that efficient trafficking of defective HIV-1 vectors<br />
is observed in vitro and the following superinfection<br />
with wild type HIV-1 and that such<br />
trafficking results in a marked inhibition of wild<br />
type viral spread.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Lancet, JE, Rosenblatt, JD , and Karp, JE.<br />
Farnesyltransferase inhibitors and myeloid malignancies:<br />
phase I evidence of Zarnestra activity in<br />
high-risk leukemias. Seminars in Hematology<br />
39:31-35, 2002.<br />
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,<br />
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,<br />
JD. Herpes simplex virus (HSV) amplicon-mediated<br />
codelivery of secondary lymphoid tissue<br />
chemokine and CD40L results in augmented antitumor<br />
activity. <strong>Cancer</strong> Research 62:6545-51,<br />
2002.<br />
Rosenblatt, JD , Shin, SU, Nechustan, H, Yi,<br />
KH, and Tolba, K. Potential role of chemokines<br />
in immune therapy of cancer. Israel Medical Association<br />
Journal 4:1054-59, 2002.<br />
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,<br />
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD .<br />
HSV amplicon mediated-delivery of LIGHT enhances<br />
the antigen-presenting capacity of chronic<br />
lymphocytic leukemia. Molecular Therapy 6:455-<br />
63, 2002.<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
Andela, VB, Rosenblatt, JD , Schwarz, EM, Puzas,<br />
EJ, O’Keefe, RJ, and Rosier, RN. Synergism of<br />
aminobisphosphonates and farnesyl transferase<br />
inhibitors on tumor metastasis. Clinical Orthopaedics<br />
and Related Research 397:228-39, 2002.<br />
2003<br />
Khorana, AA, Rosenblatt, JD , Sahasrabudhe,<br />
DM, Evans, T, Ladrigan, M, Marquis, D, Rosell,<br />
K, Whiteside, T, Phillippe, S, Acres, B, Slos, P,<br />
Squiban, P, Ross, M, and Kendra, K. A phase I<br />
trial of immunotherapy with intratumoral adenovirus-interferon-gamma<br />
(TG1041) in patients<br />
with malignant melanoma. <strong>Cancer</strong> Gene Therapy<br />
10:251-9, 2003.<br />
Andela, VB, Pirri, M, Schwarz, EM, Puzas, EJ,<br />
O’Keefe, RJ, Rosenblatt, JD, and Rosier, RN.<br />
The mevalonate synthesis pathway as a therapeutic<br />
target in cancer. (Review) Clinical Orthopaedics<br />
415 (Supplement): S59-66, 2003.<br />
Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A,<br />
Lu, C, McNair, C, Abboud, CN, and Rosenblatt<br />
JD. Effects of the farnesyl transferase inhibitor<br />
R115777 on normal and leukemic hematopoiesis.<br />
Leukemia 17:1806-12, 2003.<br />
Rosenblatt, JD and Harrington, WJ Jr. Leukemia<br />
and myelopathy: the persistent mystery of pathogenesis<br />
by HTLV-I/II. <strong>Cancer</strong> Investigation<br />
21:323-24, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Developed novel antibody-chemokine and antibody<br />
co-stimulatory ligand fusion proteins with<br />
dual function and preserved targeting capabilities.<br />
• Developed a novel strategy for gene therapy of<br />
HIV-1 using mutations introduced into<br />
tRNA LYS3 primers.<br />
• Demonstrated the potential role for HSV<br />
amplicon vectors in gene therapy of malignancy,<br />
particularly CLL.<br />
• Demonstrated trafficking and inhibition by<br />
defective HIV-1 as a novel approach to HIV-1<br />
gene therapy.<br />
• Demonstrated the utility of combining<br />
chemokine delivery with costimulating ligands<br />
in augmenting mouse response to tumors.<br />
GIOVANNA R. THOMAS, M.D.<br />
Assistant Professor of Otolaryngology<br />
DESCRIPTION OF RESEARCH<br />
Head and neck squamous cell carcinoma<br />
(HNSCC) of the upper aerodigestive tract is<br />
a devastating disease that impacts human communication<br />
and survival. Lack of effective immune<br />
responses is important in the progression<br />
of HNSCC and is a prognostic marker for poor<br />
clinical response and decreased survival. The<br />
long-range goal of Dr. Thomas’ research is to develop<br />
novel therapeutic modalities to improve<br />
anti-tumor immunity in patients with HNSCC<br />
who continue to have disappointingly low survival<br />
rates despite aggressive treatments. The<br />
CD80/CD28 co-stimulation pathway is critical<br />
for T-cell activation and proliferation. It has been<br />
well documented in the literature that engagement<br />
of CD80 on antigen-presenting cells by its<br />
receptor CD28 on T cells leads to multiple effects<br />
on immune responses in addition to increasing<br />
the synthesis of autocrine growth factors such as<br />
interleukin-2 (IL-2). To date, however, not much is<br />
known regarding the role of CD80 co-stimulatory<br />
molecules in generating anti-tumor immune responses<br />
against tumors formed from epithelial cells.<br />
Dr. Thomas’ objective is to determine the<br />
role and regulation of the CD80 co-stimulatory<br />
molecule during tumor progression of HNSCC.<br />
Her laboratory has previously characterized the<br />
expression of CD80 in different murine HNSCC<br />
clones derived naturally following tumor progression<br />
in the absence of T cell-mediated immunity<br />
in severe combined immune deficient (SCID)<br />
mice. Exciting features observed during their<br />
study were that HNSCC that did not express<br />
CD80 grew as progressors, while those that expressed<br />
CD80 were regressors when grown in immune<br />
competent animals. Preliminary data show<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 123
T U M O R I M M U N O L O G Y P R O G R A M<br />
CD80-mediated T-cell dependent anti-tumor<br />
immunity and the generation of protective immunity<br />
in animals are resistant to rechallenge. In<br />
addition, they found that constitutive expression<br />
of one or more of the cytokines IL-1α, IL-6, and<br />
GM-CSF is associated with down-modulation of<br />
CD80 co-stimulatory molecule expression in oral<br />
HNSCC cells. The HNSCC cell lines that exhibit<br />
a combination of constitutive cytokine expression<br />
and low CD80 expression also exhibit<br />
increased tumorigenic potential in immune-competent<br />
mice, as previously reported. Reduction of<br />
CD80 co-stimulatory molecule expression by<br />
pro-inflammatory cytokines IL-1α, IL-6, and<br />
GM-CSF has not been previously described. This<br />
decrease in CD80 expression during malignant<br />
progression of HNSCC may result in dysfunctional<br />
anti-tumor immunity, thereby promoting<br />
malignant growth.<br />
Studies are under way to determine the regulatory<br />
mechanisms of cytokine-induced downregulation<br />
of CD80 expression and to determine<br />
the prognostic significance of its expression on<br />
tumor specimens from patients with HNSCC.<br />
Once the role and regulation of CD80 in<br />
HNSCC are understood, CD80 expression can<br />
be up-regulated pharmacologically in new and<br />
innovative approaches to increase anti-tumor immune<br />
responses for the prevention and treatment<br />
of HNSCC.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Thomas, GR, Regalado, JJ, and McClinton, M.<br />
A rare case of mucoepidermoid carcinoma of the<br />
nasal cavity. Ear, Nose, and Throat Journal<br />
81:519-22, 2002.<br />
2003<br />
Pandey, M, Chandramohan, K, Thomas, G,<br />
Mathew, A, Sebastian, P, Somanathan, T,<br />
Abraham, EK, Rajan, B, and Krishnan Nair, M.<br />
Soft tissue sarcoma of the head and neck region<br />
in adults. International Journal of Oral and Maxillofacial<br />
Surgery 32:43-48, 2003.<br />
124<br />
KHALED TOLBA, M.D.<br />
Assistant Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
During the past five years, Dr. Tolba has been<br />
developing immunotherapeutic strategies for<br />
B-cell hematologic malignancies, with particular<br />
interest in chronic lymphocytic leukemia (CLL).<br />
CLL is the most common leukemia in the Western<br />
hemisphere. As a relatively slow-progressing<br />
tumor with readily accessible tumor cells, it offers<br />
an opportunity to develop and test immunotherapeutic<br />
interventions. A number of profound<br />
immunologic deficiencies affecting both the B-<br />
and T-cell responses, however, have posed a challenge<br />
to immune therapy of CLL.<br />
The laboratory has co-developed and<br />
adapted the use of herpes simplex virus (HSV)<br />
amplicons for gene transduction of CLL cells.<br />
Using CD40L as an effector molecule, they have<br />
shown robust induction of co-stimulatory molecules<br />
on transduced and bystander cells<br />
and in roughly one-third of tested patients<br />
demonstrated the capacity to generate cytotoxic<br />
T lymphocyte (CTL) activity. This capacity to<br />
elicit autologous CTL response, however, was not<br />
universal as more than half the patients tested<br />
failed to mount such a response in spite of adequate<br />
up-regulation of co-stimulatory signal on<br />
both transduced and bystander CLL cells. In addition<br />
to being a highly efficient gene transfer vector,<br />
herpes simplex virus (HSV)-based amplicons<br />
possess the capacity to engage and activate different<br />
elements of the innate immune system. Currently,<br />
the laboratory is studying various aspects of HSV<br />
amplicon/innate immune interaction and their<br />
influence on the outcome of an adaptive antitumor<br />
immune response.<br />
Immune therapeutic strategies targeting the<br />
innate immune system might offer an alternative<br />
pathway to bypass inherent CD8 + T-cell defects<br />
and effectively mount a systemic anti-tumor immune<br />
response. Dr. Tolba and his colleagues are<br />
exploring how HSV amplicon interacts with the<br />
family of toll-like (TL) receptors and up-regulates<br />
NKG2D ligands on target cells.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
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SELECTED PUBLICATIONS<br />
2002<br />
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,<br />
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD.<br />
Herpes simplex virus (HSV)-amplicon-mediated<br />
delivery of LIGHT enhances the antigen-presenting<br />
capacity of chronic lymphocytic leukemia.<br />
Molecular Therapy 6:455-63, 2002.<br />
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,<br />
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,<br />
JD. Herpes simplex virus (HSV) amplicon-mediated<br />
codelivery of secondary lymphoid tissue<br />
chemokine and CD40L results in augmented antitumor<br />
activity. <strong>Cancer</strong> Research 62:6545-51,<br />
2002.<br />
Rosenblatt, JD, Shin, SU, Nechustan, H, Yi,<br />
KH, and Tolba, K. Potential role of chemokines<br />
in immune therapy of cancer. Israel Medical<br />
Association Journal 4:1054-59, 2002.<br />
MARTA TORROELLA-KOURI, PH.D.<br />
Assistant Professor of Microbiology<br />
and Immunology<br />
DESCRIPTION OF RESEARCH<br />
When tumor cells initially emerge in a<br />
healthy organism, they are recognized by<br />
the immune system. This recognition leads to an<br />
incipient defense reaction and elimination of the<br />
initial tumor cell population. For unknown reasons,<br />
however, some tumors progress, infiltrate,<br />
and eventually metastasize and kill the host. Before<br />
this occurs, a progressive decline in the immune<br />
response of the host is observed. Today,<br />
researchers know that the tumor is directly responsible<br />
for this immunodepression observed in<br />
tumor-bearing organisms.<br />
The study of the interplay between a tumor<br />
and its host, in terms of the mechanisms displayed<br />
by the tumor that eventually control and<br />
diminish the otherwise healthy immune response<br />
of the host organism, is the center of Dr.<br />
Torroella-Kouri’s research. She is particularly interested<br />
in the role of the innate immune response<br />
in cancer. Researchers in her laboratory<br />
work with a mouse mammary tumor model in<br />
which they observe a profound decrease in the<br />
immune response of tumor-bearing animals. Specifically,<br />
and among many other events, a deregulation<br />
in the production of cytokines, important<br />
mediators in cell-to-cell communication, is observed.<br />
One of them, the critical cytokine<br />
interleukin-12 (IL-12), produced by macrophages<br />
and dendritic cells (DC), is seriously decreased in<br />
the diseased animals. IL-12 has not only been<br />
shown to play a central role in the communication<br />
between the innate and induced immune<br />
responses, but also recently has been the center of<br />
much clinical interest due to its recognized antitumor<br />
properties.<br />
The laboratory has shown that several mammary<br />
tumor-derived factors appear to be responsible<br />
for the decreased production of IL-12 in the<br />
tumor host. Their present research focuses particularly<br />
in elucidating the mechanisms through<br />
which the tumor-derived phospholipid phosphatidylserine,<br />
as well as the cytokine IL-6, overproduced<br />
in tumor-bearing animals, are able to<br />
impair IL-12 expression in tumor animals. The<br />
understanding of the molecular mechanisms governing<br />
the expression of the critical cytokine IL-<br />
12 in the context of the interaction between a<br />
tumor and the immune system is essential in efforts<br />
aimed at designing therapeutic strategies to<br />
treat malignant disorders. Given its many roles,<br />
direct applications of IL-12 or modulation of IL-<br />
12 levels will remain an important aspect of research<br />
for the treatment of cancer. The<br />
laboratory’s tumor system, which like in the human<br />
situation presents a severe impairment of IL-<br />
12 production, is an excellent model in which to<br />
design future translational research.<br />
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SELECTED PUBLICATIONS<br />
2003<br />
Torroella-Kouri, M and Lopez, D. Mammary<br />
tumor derived TGF-β impairs crucial innate immune<br />
responses in tumor hosts. Journal of Immunology<br />
and Immunopathology 5:31-38, 2003.<br />
Torroella-Kouri, M , Keith, JC, Ivanova, M, and<br />
Lopez, DM. IL-11-induced reduction of C/EBP<br />
transcription factor binding may contribute to<br />
the IL-12 down-regulation in tumor-bearing<br />
mice. International Journal of Oncology 22:439-<br />
48, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Focused on the tumor-induced mechanisms<br />
that explain the impaired expression of IL-12 in<br />
the macrophages of the mice bearing the D1-<br />
DMBA-3 mammary tumor.<br />
• Demonstrated that indeed there is a decreased<br />
IL-12 production in elicited peritoneal macrophages<br />
from tumor-bearing mice, both at the<br />
level of the protein (ELISA) as well as at the<br />
level of the gene (RT-PCR and Northern blot).<br />
They have shown that the expression of gene<br />
p40 is profoundly decreased, although gene p35<br />
has a slightly diminished expression as well in<br />
macrophages of tumor bearers (IL-12 is a<br />
heterodimer comprised of two independently<br />
regulated genes, p40 and p35).<br />
• Demonstrated that in message stability experiments<br />
there is no difference in the mRNA stability<br />
of the p40 message between normal and<br />
tumor-bearing animals, meaning that the regulation<br />
of the deficiency seems not to be posttranscriptional.<br />
• Electromobility shift assays (EMSAs) with<br />
nuclear extracts of macrophages from normal<br />
and tumor animals have shown that of several<br />
transcription factors that appear to be relevant<br />
in the transcription of the p40 gene, there is a<br />
diminished binding activity of NFκB and<br />
C/EBP transcription factors to their sites in the<br />
p40 promoter of tumor-bearing animals. It is<br />
known that there are several factors produced<br />
by the D1-DMBA-3 tumor that are able to<br />
down-regulate IL-12. Among these,<br />
phopsphatidylserine and prostaglandin E2,<br />
which are produced by this tumor, have been<br />
shown to down-regulate IL-12 in macrophages<br />
of normal mice pretreated with these factors.<br />
• Demonstrated that this mammary tumor produces<br />
the anti-inflammatory and metastasispromoting<br />
cytokine IL-11, and that IL-11<br />
decreases IL-12 production as well, by diminishing<br />
the expression of p40 gene (RT-PCR).<br />
Researchers in her laboratory also have demonstrated<br />
that IL-11 decreases the binding activity<br />
of the C/EBP transcription factor, but not that<br />
of NFκB to the p40 promoter in tumor bearing<br />
animals.<br />
• Demonstrated that the immunosuppressor<br />
cytokine transforming growth factor-beta<br />
(TGF-β) also is produced by the D1-DMBA-3<br />
tumor, as well as by macrophages and T cells<br />
from these tumor-bearing animals. TGF-β also<br />
is known to down-regulate IL-12. On the other<br />
hand, macrophages and B cells from tumorbearing<br />
animals overproduce the cytokines IL-6<br />
and tumor necrosis factor-alpha (TNF-α).<br />
TNF-α is known to down-regulate IL-12, and<br />
her laboratory has been able to demonstrate<br />
that IL-6 decreases the production of this<br />
cytokine as well. Therefore, there are different<br />
tumor-associated factors that could be playing a<br />
role in the impairment of IL-12 production in<br />
the laboratory’s tumor model. Some of their<br />
mechanisms have been worked out.<br />
• Observed that two of these molecules, the phospholipid<br />
PS and the cytokine IL-6 are novel<br />
modulators of this important cytokine. Dr.<br />
Torroella-Kouri plans to focus her laboratory’s<br />
immediate research efforts on the elucidation<br />
of the molecular mechanisms by which these<br />
molecules down-regulate the expression of the<br />
IL-12 genes.<br />
126<br />
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T U M O R I M M U N O L O G Y P R O G R A M<br />
• Currently studying the expression of IL-12<br />
receptor in the T cells from tumor bearers, in<br />
order to determine if the decreased levels of<br />
IFN-gamma observed in T cells from tumor<br />
bearers might also be explained in part because<br />
of a low level of expression of this receptor, in<br />
addition to low levels of IL-12. IL-12 is known<br />
to stimulate the production of interferongamma<br />
(IFN-γ) in naïve T cells.<br />
VLADIMIR VINCEK, M.D., PH.D.<br />
Associate Professor of Pathology<br />
DESCRIPTION OF RESEARCH<br />
Progress in the understanding of molecular<br />
events involved in the development and progression<br />
of human disease is revolutionizing the<br />
way diseases are diagnosed and treated. Physicians<br />
and scientists now are harnessing the power of<br />
molecular techniques to diagnose and prognosticate<br />
pathologic disorders. Furthermore, it is now<br />
possible to direct therapeutic agents to specific<br />
products expressed by diseased cells without affecting<br />
normal tissues. On the other hand, while<br />
standard histopathologic methods maintain tissue<br />
architecture for morphologic assessment, they do<br />
not preserve macromolecules. The extraction of<br />
nucleic acids from formaldehyde-fixed, paraffinembedded<br />
tissue, the most widely available material<br />
for clinical studies, is a notoriously unreliable<br />
and irreproducible process. Therefore, macromolecules<br />
usually are extracted from fresh or snapfrozen<br />
tissue specimens. Fresh or frozen tissue<br />
specimens, however, have limited value for the<br />
assessment of histomorphology and cannot be<br />
utilized for long-term retrospective studies. Similarly,<br />
currently available tissue preservatives that<br />
protect nucleic acids cause considerable damage<br />
to the cell and tissue architecture and render<br />
them unsuitable for histomorphologic evaluation.<br />
Current studies in this laboratory show that<br />
it is feasible to simultaneously protect histomorphology<br />
and the integrity of macromolecules<br />
in fixed and processed tissue. The UMFIX<br />
reagent, developed in collaboration with other<br />
members of the Department of Pathology, seems<br />
to provide enormous advantage over the conventional<br />
fixation methods in allowing diagnosis,<br />
prognostication, and identification of treatment<br />
targets in patient samples.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Malek, TR, Yu, A, Vincek, V, Scibelli, P, and<br />
Kong, L. CD4 regulatory T cells prevent lethal<br />
autoimmunity in IL-2Rbeta-deficient mice. Implications<br />
for the nonredundant function of IL-2.<br />
Immunity 17:167-78, 2002.<br />
Morales, A, Essenfeld, H, Dubane, C, Vincek, V,<br />
and Nadji, M. Continuous-specimen flow, highthroughput,<br />
1-hour tissue processing. Archives of<br />
Pathology & Laboratory Medicine 126:584-90,<br />
2002.<br />
2003<br />
Vincek, V, Knowles, J, and Nassiri, M. p63<br />
mRNA expression in normal human tissue. Anticancer<br />
Research 23:3945-48, 2003.<br />
Jacob, SE, Nassiri, M, Kerdel, FA, and Vincek, V.<br />
Rapid measurement of multiple cytokines in psoriasis<br />
patients and correlation with disease severity.<br />
Mediators of Inflammation 12:309-13, 2003.<br />
Adkins, B, Bu, Y, Vincek, V, and Guevara, P. The<br />
primary responses of murine neonatal lymph<br />
node CD4 + cells are Th2-skewed and are sufficient<br />
for the development of Th2-biased memory.<br />
Clinical & Developmental Immunology 10:43-<br />
51, 2003.<br />
Vincek, V, Nassiri, M, Nadji, M, and Morales,<br />
AR. A novel tissue preservative that protects macromolecules<br />
(DNA, RNA, protein) and histomorphology<br />
in clinical samples. Laboratory<br />
Investigation 83:1-9, 2003.<br />
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Jacob, SE, Berman, B, Nassiri, M, and Vincek, V.<br />
Topical application of imiquimod 5% cream to<br />
keloids alters expression genes associated with<br />
apoptosis. The British Journal of Dermatology<br />
149:1-4, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Applied for a patent for an alcohol-based<br />
UMfix preservative that preserves histomorphology<br />
and macromolecules; the patent<br />
currently is pending.<br />
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V I R A L O N C O L O G Y P R O G R A M<br />
V I R A L O N C O L O G Y P R O G R A M<br />
PROGRAM LEADERS<br />
William J. Harrington, Jr., M.D.<br />
Professor of Medicine<br />
Glen N. Barber, Ph.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF PROGRAM<br />
The Viral Oncology Program currently consists<br />
of faculty members from five different departments<br />
at the University of Miami School of<br />
Medicine. The principal objective of this program<br />
is to promote clinical and basic investigation of<br />
oncogenic viruses. The investigators were recruited<br />
on the basis of productive track records in<br />
their respective disciplines and a commitment to<br />
innovative and complementary research.<br />
Each investigator studies a particular aspect<br />
of cancer biology and therapy such as apoptosis,<br />
DNA replication and repair, mechanisms of<br />
cytokines, interferons and oncolytic viruses,<br />
membrane transport, and experimental therapeutics.<br />
This has resulted in the formation of an integrated,<br />
collaborative effort where each member<br />
provides an important, yet distinct, contribution.<br />
The program also is committed to the development<br />
of physician-scientists and basic researchers<br />
in the field of viral oncology.<br />
Bench research conducted by members of<br />
this program has translated into novel clinical<br />
trials. A forum for such experimental trials exists<br />
through the NIH-sponsored AIDS Malignancy<br />
Consortium (AMC), and the University of<br />
Miami <strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> is<br />
a fully funded independent member. National<br />
trials for AIDS-related central nervous system<br />
lymphoma, AMC 019, originated at the University<br />
of Miami School of Medicine. The program is<br />
developing pre-clinical models for cancer therapy<br />
by utilizing oncolytic viruses as targeted anti-cancer<br />
and immuno-therapeutic agents. Program members<br />
also are investigating the basic mechanisms<br />
of lympho-magenesis by focusing on cytokine<br />
dependence (IL-6), pro- and anti-apoptotic gene<br />
expression, viral interactions with transcription<br />
factors, and the effect of viruses on nuclear membrane<br />
transport.<br />
There is a concerted effort to extend pathogenesis-based<br />
studies and therapeutic trials of viral<br />
malignancies to developing nations such as Zambia<br />
and Brazil. These efforts are funded through<br />
Fogarty grants and the NCI. A principal goal is to<br />
establish the University of Miami as a preeminent<br />
center for international studies of viral oncology.<br />
UM/<strong>Sylvester</strong>, with its diverse patient base<br />
and large numbers of cases of HIV gamma<br />
herpesvirus and human T-lymphotropic virus<br />
type I (HTLV-I) associated tumors, is the ideal<br />
site for the study of viral oncology.<br />
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GOALS OF PROGRAM<br />
1) Investigate the regulation of programmed cell<br />
death, membrane transport, interferons,<br />
cytokines, and viral and cellular gene expression<br />
in cancers that arise in immunocompromised<br />
patients.<br />
2) Devise novel therapeutic strategies for therapy<br />
of viral malignancies.<br />
3) Train investigators in the field of viral oncology<br />
and extend our basic and clinical studies<br />
to developing nations with a high incidence of<br />
viral-induced malignancies.<br />
PARTICIPANTS<br />
Barber, Glen N., Ph.D.<br />
Microbiology and Immunology<br />
Boehmer, Paul E., Ph.D.<br />
Biochemistry and Molecular Biology<br />
Boise, Lawrence H., Ph.D.<br />
Microbiology and Immunology<br />
Byrne, Jr., Gerald E., M.D<br />
Pathology<br />
Fontoura, Beatriz M.A., Ph.D.<br />
Molecular and Cellular Pharmacology<br />
Harhaj, Edward W., Ph.D.<br />
Microbiology and Immunology<br />
Harrington, Jr., William J., M.D.<br />
Medicine<br />
Mian, Abdul M., Ph.D.<br />
Medicine<br />
So, Antero G., M.D., Ph.D.<br />
Medicine<br />
HIGHLIGHTS<br />
Basic/Translational Research<br />
• Glen N. Barber, Ph.D., and his colleagues study<br />
the mechanisms of host defense against viral<br />
and malignant disease. Their research focuses<br />
on elucidating the mechanisms of interferons<br />
including their role in regulating apoptosis.<br />
These researchers recently have demonstrated<br />
that vesicular stomatitis virus (VSV), an essentially<br />
nonpathogenic negative-stranded RNA<br />
virus, can selectively induce the cytolysis of numerous<br />
transformed human cell lines in vitro.<br />
The ability of these viruses to selectively kill<br />
tumor cells and not normal cells was dependent<br />
on the protein kinase R/interferon (PKR/IFN)<br />
pathway being defective in susceptible cells.<br />
They have now demonstrated in vivo that tumors<br />
defective in p53 function or transformed<br />
with myc or activated ras also are susceptible to<br />
viral cytolysis, and that the mechanism of viral<br />
oncolytic activity involves the induction of multiple<br />
caspase-dependent apoptotic pathways.<br />
Furthermore, VSV caused significant inhibition<br />
of tumor growth when administered intravenously<br />
in immunocompetent hosts. Their findings<br />
suggest that VSV could be used as a<br />
potential oncolytic agent against a wide variety<br />
of malignant diseases associated with a diversity<br />
of genetic defects. Extensions of this work now<br />
include engineering VSV to express proteins<br />
from viruses associated with cancer such as<br />
hepatitis C (HCV) and human papilloma virus<br />
(HPV) for vaccine and therapeutic purposes.<br />
For example, chimeric VSV containing HCV<br />
structural proteins is being examined as a therapeutic<br />
or preventative vaccine.<br />
• William J. Harrington, Jr., M.D., investigates<br />
the use of antiviral agents in viral-induced malignancies.<br />
He has found that antiviral thymidine<br />
analogues such as azidothymidine (AZT)<br />
and IFN α induce marked apoptosis in Epstein-<br />
Barr virus (EBV) and human herpes virus type<br />
8 (HHV-8)-associated primary effusion lymphomas<br />
(PELs). This therapy was very effective<br />
in eradicating AIDS-related brain lymphoma<br />
and formed the basis for a nationwide clinical<br />
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V I R A L O N C O L O G Y P R O G R A M<br />
trial. His data demonstrate that IFN α potently<br />
induces the death receptor ligand TRAIL. AZT<br />
is phosphorylated by the herpes virus thymidine<br />
kinase and acts by blocking NF-κB (p50, p65)<br />
translocation into the nucleus allowing for an<br />
unopposed death signal. AZT also down-regulates<br />
the expression of anti-viral, anti-apoptotic<br />
proteins such as vFLIP. A similar mechanism<br />
has been shown to occur in other viral-induced<br />
tumors such as post-transplant lymphoma<br />
(EBV). Dr. Harrington and his colleagues have<br />
initiated a new clinical trial for HHV-8-associated<br />
lymphomas that utilizes parenteral AZT<br />
and IFN α (these tumors virtually are always<br />
fatal). The first patient enrolled has remained in<br />
complete remission for more than two years.<br />
AZT-mediated blockade of NF-κB is a potentially<br />
exciting novel strategy that combines both<br />
anti-HIV and EBV activity. The target malignancy<br />
(and one of the most common worldwide)<br />
for this type of approach is endemic<br />
Burkitt’s lymphoma. Current studies focus on<br />
understanding the specificity of this therapy for<br />
herpes virus-associated lymphomas, the development<br />
of more potent antiviral antilymphoma<br />
thymidine analogues, and the extension of this<br />
approach to other gamma herpes and lymphomas<br />
that occur in the immunocompromised<br />
patients (post-transplant, hereditary immunodeficiencies).<br />
This work is done in collaboration<br />
with Abdul M. Mian, Ph.D., and Ram Agarwal,<br />
Ph.D. Dr. Harrington also recently received a<br />
NCI-funded career award (K24), which will<br />
enable him to focus on the above described<br />
laboratory and clinical studies.<br />
• Antero G. So, M.D., Ph.D., and Kathleen M.<br />
Downey, Ph.D., recently have identified a novel<br />
protein, polymerase delta interacting protein<br />
(PDIP1). This protein interacts with the small<br />
subunit (p50) of DNA polymerase delta (the<br />
primary polymerase responsible for cell growth<br />
and differentiation) and the proliferating cell<br />
nuclear antigen (PCNA). PDIP1 colocalizes<br />
with pol delta and PCNA at replication foci in<br />
the nuclei of S-phase cells and stimulates its<br />
activity (in the presence of PCNA). The expression<br />
of PDIP1 can be induced by the cytokines<br />
tumor necrosis factor alpha (TNF-α) and IL-6.<br />
PDIP1 is a distal target of IL-6. There is increasing<br />
evidence suggesting that the cytokine<br />
IL-6 plays an important role in the pathogenesis<br />
of certain types of AIDS-related lymphomas.<br />
Recent studies strongly have implicated a critical<br />
role for IL-6 in EBV-dependent lymphoproliferative<br />
disease. It also has been reported<br />
that the development of AIDS-associated<br />
Burkitt’s/small non-cleaved cell lymphoma is<br />
preceded by elevated serum levels of IL-6. In<br />
addition, cell lines derived from HHV-8-associated<br />
AIDS primary effusion lymphomas constitutively<br />
secrete high levels of both IL-6 and the<br />
HHV-8 IL-6 homologue (vIL-6). Consistent<br />
with these findings is the observation that the<br />
inhibition of NF-κB (by AZT or other inhibitors)<br />
down-regulates cytokine IL-6 and induces<br />
apoptosis in Karposi’s sarcoma-associated herpes<br />
virus (KSHV) infected cells.<br />
• Researchers in Lawrence H. Boise, Ph.D.’s laboratory<br />
investigate factors that regulate the pathways<br />
associated with death receptor-induced<br />
apoptosis. Previous studies have indicated that<br />
cells can utilize one of two pathways to propagate<br />
death signals resulting from the ligation of<br />
the TNF receptor as well as from CD95 (Fas/<br />
Apo-1). Cells referred to as type I cells can activate<br />
a caspase cascade that does not require release<br />
of factors from the mitochondria.<br />
Expression of anti-apoptotic proteins Bcl-2 or<br />
Bcl-x L<br />
is incapable of inhibiting death receptor<br />
signaling in type I cells. In contrast, death receptor<br />
signaling in type II cells requires release<br />
of mitochondrial factors and is inhibited by<br />
Bcl-2/x L<br />
expression. Dr. Boise has demonstrated<br />
that cells can utilize both type I and type II signals<br />
and that Bcl-2/x L<br />
can affect type I death<br />
receptor signaling when used in concert with<br />
inhibitors of signaling caspases. Interestingly, γ-<br />
herpes viruses associated with Karposi’s sarcoma<br />
and PELs encode both a Bcl-2 homologue as<br />
well as an inhibitor of CD95 signaling (vFlip).<br />
While it has been previously suggested that viruses<br />
express these molecules to block distinct<br />
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V I R A L O N C O L O G Y P R O G R A M<br />
death pathways, based on his results it is hypothesized<br />
that vBcl-2 and vFlip may work in<br />
concert to block complex death receptor signaling.<br />
Researchers currently are testing this hypothesis<br />
through the introduction of these<br />
genes into TNF-α-sensitive cell lines as well as<br />
inhibiting expression of virally expressed genes<br />
in PEL cell lines. This work is being carried out<br />
primarily by M.D./Ph.D. student Esther<br />
Obeng. Ms. Obeng has received a Howard<br />
Hughes Medical Institute Fellowship to support<br />
her research. This work is the basis of collaboration<br />
with William J. Harrington, Jr., M.D., on<br />
his studies to determine the mechanisms of<br />
anti-viral induced apoptosis in AIDS-related<br />
lymphomas that appear to be death receptor<br />
mediated.<br />
• Beatriz M.A. Fontoura, Ph.D.’s laboratory<br />
works on the signal-mediated nuclear import<br />
and export of molecules that occurs through<br />
nuclear pore complexes (NPC). These are<br />
highly regulated pathways that control nuclear<br />
entry and exit of molecules such as transcription<br />
factors, RNAs, kinases, and viral particles.<br />
NPCs are composed of proteins termed<br />
nucleoporins or Nups, which have a role in the<br />
structure of the NPC and also in regulating<br />
translocation of molecules through the NPC.<br />
Nups are targets of viral proteins and disruption<br />
of Nup function is involved in cancer. Dr.<br />
Fontoura has identified and characterized two<br />
major Nups—Nup98 and Nup96—which are<br />
key controllers of nuclear entry and exit of proteins<br />
and RNAs. The Nup98-Nup96 pathway<br />
is highly regulated by specific signaling pathways,<br />
is a target of viral proteins, and is involved<br />
in tumorigenesis. The goal of the<br />
investigators working in this laboratory is to<br />
understand the molecular mechanisms of the<br />
nuclear transport machinery and how they are<br />
regulated by different signaling pathways and<br />
viruses. The discovery of novel mechanisms or<br />
factors of this pathway are important for controlling<br />
cell growth and also may serve as therapeutic<br />
targets.<br />
• Edward W. Harhaj, Ph.D.’s laboratory studies<br />
viral-induced malignancy by the human T-cell<br />
leukemia virus type I (HTLV-I). HTLV-I is associated<br />
with several diseases including adult T-<br />
cell leukemia (ATL) and a neurological disorder<br />
known as HTLV-I-associated myelopathy/tropical<br />
spastic paraparesis (HAM/TSP). HTLC-I<br />
encodes a trans-activating protein, Tax, which<br />
has pleiotropic functions and is highly oncogenic.<br />
Tax activates cellular signaling pathways<br />
and transcription factors, such as NF-κB, resulting<br />
in global changes in gene expression.<br />
NF-κB is a family of dimeric DNA-binding<br />
proteins that regulates the expression of genes<br />
that control a variety of cellular functions such<br />
as activation, differentiation, survival, and effector<br />
function. A major effort of Dr. Harhaj’s<br />
laboratory is to elucidate the mechanisms utilized<br />
by Tax to activate the NF-κB signaling<br />
pathway. Toward this end, researchers are identifying<br />
cellular proteins that interact with Tax<br />
and are examining the role of these proteins in<br />
Tax-medicated NF-κB activation and cellular<br />
transformation.<br />
An example of how the laboratories interact is<br />
demonstrated in the illustration on page 133.<br />
Each group addresses a distinct area relevant to<br />
viral lymphomagenesis.<br />
Training and International Effort<br />
The laboratories of Dr. Harrington and Charles<br />
Wood, Ph.D., (University of Nebraska) have a<br />
long-standing relationship in AIDS-associated<br />
malignancies and currently collaborate on two<br />
R01-funded research projects and two Fogarty<br />
International Training Programs. These research<br />
projects center around the molecular epidemiology<br />
of the transmission of HHV-8 and EBV and<br />
the role these viruses play in the induction of malignancies.<br />
The objectives of these projects are: 1)<br />
determine the factors associated with transmission<br />
of HHV-8 in Zambia and its relationship on<br />
progression to AIDS, 2) develop an NCI-sponsored<br />
research repository in Brazil and Africa,<br />
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V I R A L L Y M P H O M A<br />
3) initiate clinical trials for AIDS-related malignancies<br />
in Brazil, and 4) study the molecular<br />
tumor pathogenesis of viral lymphomas in Africa<br />
and Brazil.<br />
Researchers in the Viral Oncology Program<br />
recently collaborated with Dr. Carlos Brites (Brazil)<br />
and successfully obtained funding through<br />
Fogarty to establish a viral oncology training program<br />
in Salvador, Brazil. Such studies are critical<br />
to understanding and developing rational therapy<br />
for malignancies in immunocompromised patients.<br />
The program recently was funded through<br />
the NCI for a study of inhibition of NF-κB and<br />
disruption of latency in high-grade primary lymphomas<br />
derived from Brazilian patients. Juan<br />
Carlos Ramos, M.D., (University of Miami) received<br />
a supplemental NCI grant linked to the<br />
AMC parent grant for a molecular study of PELs.<br />
In collaboration with the Federal University of<br />
Bahia in Brazil, a five-year training grant for<br />
AIDS/oncology was submitted. Bahia is a unique<br />
area that principally is populated by descendants<br />
of West Africa and is endemic for HTLV-I. The<br />
majority of non-Hodgkin’s lymphomas are associated<br />
with EBV or HTLV-I. Therefore, this presents<br />
an outstanding opportunity for clinical and<br />
basic investigation of these illnesses.<br />
Zambia is a central African nation located in<br />
the “AIDS and tumor belt.” In order to support<br />
their research activities in Zambia, the University<br />
of Nebraska at Lincoln, under Dr. Wood, and the<br />
University of Miami under Dr. Harrington and<br />
Charles D. Mitchell, M.D., have developed a successful<br />
training and research collaboration with<br />
the University of Zambia School of Medicine and<br />
the University Teaching Hospital, under the auspices<br />
of the Zambian Ministry of Health. This<br />
program, funded through the Fogarty International<br />
Post-Doctoral Training Program in HIV/<br />
AIDS, has provided instruction to Zambian<br />
health care personnel in clinical, epidemiological,<br />
and basic science research methodology at both<br />
the Universities of Miami and Nebraska.<br />
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GLEN N. BARBER, PH.D.<br />
Professor of Microbiology and Immunology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Barber’s research focuses on understanding<br />
the mechanisms of innate immunity to viral<br />
infection and malignant disease. Specifically, one<br />
area of research in his laboratory aims to understand<br />
the mechanisms by which the interferons<br />
(IFNs) mediate their anti-viral and anti-proliferative<br />
effects. One key IFN-inducible gene is the<br />
dsRNA-dependent protein kinase PKR, which is<br />
activated upon virus infection and limits viral<br />
replication by inhibiting host cell protein translation.<br />
Researchers recently have shown that mice<br />
lacking PKR are very sensitive to lethal infection<br />
by vesicular stomatitis virus (VSV) and influenza<br />
virus, underscoring the importance of this<br />
molecule in host defense. They additionally have<br />
shown that PKR and IFN can contribute towards<br />
the induction of apoptosis in a virally infected<br />
cell. The laboratory currently is identifying new<br />
IFN-induced genes and examining their importance<br />
in cellular growth control and immunity.<br />
In addition to examining the mechanisms of<br />
innate immunity to viral infection, researchers in<br />
Dr. Barber’s laboratory are interested in studying<br />
how viruses such as hepatitis C (HCV) and<br />
human herpes virus type-8 (HHV-8) contribute<br />
towards oncogenesis. Such viruses are known to<br />
subvert key checkpoints of host-cell growth control.<br />
Understanding the mechanisms involved in<br />
these processes could lead to an improvement of<br />
current therapies as well as the identification of<br />
new therapeutic targets and of malignant disease<br />
involving these viruses.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Fernandez, M, Porosnicu, M, Markovic, D, and<br />
Barber, GN. Genetically engineered vesicular stomatitis<br />
virus in gene therapy: application for<br />
treatment of malignant disease. Journal of Virology<br />
76:895-904, 2002.<br />
Pataer, A, Vorburger, SA, Barber, GN, Chada, S,<br />
Mhashilkar, AM, Zou-Yang, H, Stewart, AL,<br />
Balachandran, S, Roth, JA, Hunt, KK, and<br />
Swisher, SG. Adenoviral transfer of the melanoma<br />
differentiation-associated gene 7 (mda7)<br />
induces apoptosis of lung cancer cells via upregulation<br />
of the double-stranded RNA-dependent<br />
protein kinase (PKR). <strong>Cancer</strong> Research<br />
62:2239-43, 2002.<br />
Grandvaux, N, Servant, MJ, tenOever, B, Sen,<br />
GC, Balachandran, S, Barber, GN, Lin, R, and<br />
Hiscott, J. Transcriptional profiling of interferon<br />
regulatory factor 3 target genes: direct involvement<br />
in the regulation of interferon-stimulated<br />
genes. Journal of Virology 76:5532-9, 2002.<br />
Vorburger, SA, Pataer, A, Yoshida, K, Barber,<br />
GN, Xia, W, Chiao, P, Ellis, LM, Hung, MC,<br />
Swisher, SG, and Hunt, KK. Role for the doublestranded<br />
RNA activated protein kinase PKR in<br />
E2F-1-induced apoptosis. Oncogene 21:6278-<br />
88, 2002.<br />
Ezelle, HJ, Markovic D, and Barber, GN. Generation<br />
of hepatitis C virus-like particles by use of<br />
a recombinant vesicular stomatitis virus vector.<br />
Journal of Virology 76:12325-34, 2002.<br />
2003<br />
Ogilvie, VC, Wilson, BJ, Nicol, SM, Morrice,<br />
NA, Saunders, LR, Barber, GN, and Fuller-Pace,<br />
FV. The highly related DEAD box RNA helicases<br />
p68 and p72 exist as heterodimers in cells.<br />
Nucleic Acids Research 31:1470-80, 2003.<br />
Saunders, LR and Barber, GN. The dsRNA<br />
binding protein family: critical roles, diverse cellular<br />
functions. The FASEB Journal 17:961-83,<br />
2003.<br />
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Obuchi, M, Fernandez, M, and Barber, GN. Development<br />
of recombinant vesicular stomatitis<br />
viruses that exploit defects in host defense to augment<br />
specific oncolytic activity. Journal of Virology<br />
77:8843-56, 2003.<br />
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,<br />
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,<br />
Cabral, L, Barber, GN, and Harrington, WJ Jr.<br />
Potentiation of TRAIL-induced apoptosis in primary<br />
effusion lymphoma through<br />
azidothymidine-mediated inhibition of NFkappa<br />
B. Blood 101:2321-7, 2003.<br />
Balachandran, S and Barber, GN. Defective<br />
translational control facilitates vesicular stomatitis<br />
virus oncolysis. <strong>Cancer</strong> Cell 5:51-65, 2003.<br />
Poroniscu, M, Mian, A, and Barber, GN. The<br />
oncolytic effect of recombinant vesicular stomatitis<br />
virus is enhanced by expression of the fusion<br />
cytosine deaminase/uracil phosphoribosyltransferease<br />
suicide gene. <strong>Cancer</strong> Research 63:8366-76, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Discovered that IFN-inducible protein kinase<br />
PKR is a critical mediator of innate immunity<br />
to a number of viruses, since mice lacking this<br />
kinase are very susceptible to lethal infection by<br />
several viruses at doses that are innocuous to<br />
wild type mice.<br />
• Discovered that VSV has potent oncolytic (antitumor)<br />
properties. Dr. Barber’s laboratory has<br />
shown that VSV replicates to high levels in tumorigenic,<br />
but not normal cells, and has identified<br />
defects in IFN signaling and translational<br />
control in tumorigenic cells as possible reasons<br />
for this uncontrolled replication.<br />
• Developed recombinant VSV that expresses<br />
other virus proteins, such as from HCV and<br />
HPV (implicated in tumorigenesis), as possible<br />
vaccines for these viruses.<br />
• Constructed VSV variants expressing suicide<br />
cassettes and immunomodulatory genes in an<br />
effort to increase the potency and specificity of<br />
VSV oncolysis.<br />
PAUL E. BOEHMER, PH. D.<br />
Associate Professor of Biochemistry and<br />
Molecular Biology<br />
DESCRIPTION OF RESEARCH<br />
Researchers in Dr. Boehmer’s laboratory are<br />
studying molecular mechanisms of replication<br />
and recombination in herpes simplex virus<br />
type-1 (HSV-1). HSV-1 serves as an excellent<br />
system in which to study DNA transactions.<br />
Hence, like eukaryotic chromosomes, the HSV-1<br />
genome contains multiple origins of replication.<br />
Replication of the HSV-1 genome is mediated by<br />
the concerted action of several virus-encoded proteins<br />
that are thought to assemble into a<br />
multiprotein complex. Several host-encoded factors<br />
have also been implicated in viral DNA replication.<br />
Furthermore, replication of the HSV-1<br />
genome is known to be closely associated with<br />
homologous recombination, which may function<br />
in the initiation of DNA replication and in maintaining<br />
genome stability. Moreover, the virusencoded<br />
enzymes also provide a system in which<br />
to investigate the interaction of DNA replication<br />
enzymes with DNA damage.<br />
HSV-1 also is the prototypic herpes virus<br />
and therefore serves as a model to understand the<br />
mechanism of replication of this class of virus. In<br />
this regard, HSV-1 is one of eight human herpes<br />
viruses that are known to cause diverse diseases<br />
ranging from cold sores and chicken pox to mononucleosis<br />
and even cancer. The high incidence of<br />
herpes viruses in the human population and the<br />
increased susceptibility of immunocompromised<br />
individuals to these viruses make them a very important<br />
public health problem. HSV-1 in particular<br />
is the cause of oro-labial lesions as well as<br />
more serious encephalitis and corneal blindness.<br />
Most recently, Dr. Boehmer’s laboratory has<br />
proposed to examine how the virus initiates replication<br />
at an origin, the role recombination plays<br />
during initiation and at later times during the<br />
replicative cycle, how leading and lagging strand<br />
DNA synthesis are coordinated at the viral replication<br />
fork, and finally, the mechanism whereby<br />
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V I R A L O N C O L O G Y P R O G R A M<br />
the viral DNA polymerase can promote translesion<br />
DNA synthesis. Collectively, the proposed studies<br />
will provide novel insight into the replication of<br />
this medically important and biologically fascinating<br />
virus. They also will serve to increase the<br />
overall knowledge of fundamental mechanisms in<br />
DNA replication and recombination.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Tanguy Le Gac, N and Boehmer, PE. Activation<br />
of the herpes simplex virus type-1 origin-binding<br />
protein (UL9) by heat shock proteins. Journal of<br />
Biological Chemistry 277:5660-6, 2002.<br />
Nimonkar, AV and Boehmer, PE. In vitro strand<br />
exchange promoted by the herpes simplex virus<br />
type-1 single strand DNA-binding protein<br />
(ICP8) and DNA helicase-primase. Journal of<br />
Biological Chemistry 277:15182-9, 2002.<br />
Villani, G, Tanguy Le Gac, N, Wasungu, L,<br />
Burnouf, D, Fuchs, RP, and Boehmer, PE. Effect<br />
of manganese on in vitro replication of damaged<br />
DNA catalyzed by the herpes simplex virus type-<br />
1 DNA polymerase. Nucleic Acids Research<br />
30:3323-32, 2002.<br />
2003<br />
Boehmer, PE and Nimonkar, AV. Herpes virus<br />
replication. IUBMB Life 55:13-22, 2003.<br />
Nimonkar, AV and Boehmer, PE. The herpes<br />
simplex virus type-1 single-strand DNA-binding<br />
protein (ICP8) promotes strand invasion. Journal<br />
of Biological Chemistry 278:9678-82, 2003.<br />
Nimonkar, AV and Boehmer, PE. On the mechanism<br />
of strand assimilation by the herpes simplex<br />
virus type-1 single-strand DNA-binding protein<br />
(ICP8). Nucleic Acids Research 31:5275-81,<br />
2003.<br />
Nimonkar, AV and Boehmer, PE. Reconstitution<br />
of recombination-dependent DNA synthesis in<br />
herpes simplex virus 1. Proceedings of the National<br />
Academy of Sciences USA 100:10201-6,<br />
2003.<br />
Boehmer, PE and Villani, G. Herpes simplex virus<br />
type-1: a model for genome transactions.<br />
Progress in Nucleic Acid Research and Molecular<br />
Biology 75:139-171, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Discovered that recombination reactions were<br />
promoted by the HSV single-strand DNA<br />
binding protein.<br />
• Reconstituted recombination-dependent DNA<br />
synthesis in a eukaryotic viral system.<br />
• Discovered that cellular heat shock proteins<br />
participate in the initiation of viral origin-specific<br />
replication.<br />
• Discovered translesion synthesis by a model<br />
eukaryotic replicative DNA polymerase.<br />
LAWRENCE H. BOISE, PH.D.<br />
Associate Professor of Microbiology and<br />
Immunology<br />
DESCRIPTION OF RESEARCH<br />
Regulation of Programmed Cell Death<br />
Programmed cell death, or apoptosis, is a process<br />
utilized by multicellular organisms to<br />
eliminate unnecessary or damaged cells without<br />
inducing an inflammatory response. The ability<br />
of inducing a cellular suicide is required for normal<br />
development and maintenance of cell number<br />
in multicellular organisms since loss of<br />
control of this process can lead to cancer, autoimmune<br />
disease, or neurodegenerative disorders in<br />
mice and humans. While the genetic studies in<br />
the nematode suggest that members of the Bcl-2<br />
family should function upstream of caspases, this<br />
result could be the consequence of two biochemical<br />
explanations—either Bcl-2 blocks caspase activation<br />
or Bcl-2 blocks the consequence of<br />
protease activation.<br />
In studies performed on a pro-B cell line,<br />
Dr. Boise and his colleagues have found<br />
cooperativity between overexpression of Bcl-2<br />
family members and inhibition of caspases in the<br />
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prevention of tumor necrosis factor (TNF)-<br />
induced cell death. Together these data suggest<br />
that the cell death pathway in mammalian cells is<br />
not likely to be a simple linear pathway as has<br />
been suggested by C. elegans genetics. They are<br />
currently using biochemical and genetic tools to<br />
dissect this pathway and to determine the interplay<br />
between the Bcl-2 family and the caspase<br />
family. Additionally, from these studies researchers<br />
have determined that many of the changes<br />
that occur to mitochondria during apoptosis are<br />
caspase dependent. These include loss of the mitochondrial<br />
membrane potential. His laboratory<br />
has determined that mitochondria must be inactivated<br />
during apoptosis to prevent excessive production<br />
of reactive oxygen species. They are<br />
currently examining the mechanisms by which<br />
caspases regulate mitochondrial function.<br />
As a product of the laboratory’s studies of<br />
bcl-x expression in drug resistant tumors, they<br />
became interested in the study of arsenic trioxide<br />
as a potential therapeutic agent in the treatment<br />
of multiple myeloma. Dr. Boise and his colleagues<br />
are studying the mechanism by which this agent<br />
can kill chemo refractory myeloma cells as well<br />
as determine the mechanisms of acquired arsenic<br />
resistance in myeloma cell lines. These studies<br />
have led to a new clinical trial initiated at<br />
UM/<strong>Sylvester</strong>. They also will gather corollary<br />
scientific information from patients on this trial.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Anderson, KC, Boise, LH, Louie, R, and<br />
Waxman, S. Arsenic trioxide in multiple myeloma:<br />
rationale and future directions. <strong>Cancer</strong><br />
Journal 8:12-25, 2002.<br />
Bahlis, NJ, McCafferty-Grad, J, Jordan-<br />
McMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,<br />
Eckman, J, Goodman, M, Fernandez, HF, Boise,<br />
LH, and Lee, KP. Feasibility and correlates of arsenic<br />
trioxide combined with ascorbic acid-mediated<br />
depletion of intracellular glutathione for the<br />
treatment of relapsed/refractory multiple myeloma.<br />
Clinical <strong>Cancer</strong> Research 8:3658-68,<br />
2002.<br />
2003<br />
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,<br />
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,<br />
Cabral, L, Barber, GN, and Harrington, WJ Jr.<br />
Potentiation of TRAIL-induced apoptosis in primary<br />
effusion lymphoma through<br />
azidothymidine-mediated inhibition of NFkappa<br />
B. Blood 101:2321-7, 2003.<br />
McCafferty Grad, J, Bahlis, N, Aguilar, T, Kratt,<br />
N, Lee, KP, and Boise, LH. Arsenic trioxide utilizes<br />
caspase dependent and caspase independent<br />
death pathways in multiple myeloma cells. Molecular<br />
<strong>Cancer</strong> Therapeutics 2:1155-64, 2003.<br />
Beaupre, DM, McCafferty Grad, J, Bahlis, NJ,<br />
Boise, LH, and Lichtenheld, MG. Farnesyl transferase<br />
inhibitors sensitize to death receptor signals<br />
and induce apoptosis in multiple myeloma cells.<br />
Leukemia & Lymphoma 44:2123-34, 2003.<br />
BEATRIZ M.A. FONTOURA, PH.D.<br />
Assistant Professor of Molecular and<br />
Cellular Pharmacology<br />
DESCRIPTION OF RESEARCH<br />
Signal-mediated nuclear import and export of<br />
molecules occurs through nuclear pore complexes<br />
(NPC). These are highly regulated pathways<br />
that control nuclear entry and exit of<br />
molecules such as transcription factors, RNAs,<br />
kinases, and viral particles. In general, to be imported<br />
or exported from the nucleus, molecules:<br />
1) bind to transport receptors, 2) are transported<br />
through NPC present in the nuclear envelope,<br />
and 3) translocate from NPC to intranuclear or<br />
cytoplasmic target sites. Although progress has<br />
been made regarding the composition and<br />
mechanisms of the nuclear transport machinery,<br />
less is known about the function and regulation<br />
of major constituents of NPC. NPC are composed<br />
of proteins termed nucleoporins or Nups,<br />
which have a role in the structure of NPC and<br />
also in regulating translocation of molecules<br />
through NPC. Nups also are target of viral<br />
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proteins and disruption of Nup function is involved<br />
in cancer.<br />
Researchers in Dr. Fontoura’s laboratory have<br />
identified and characterized two major Nups,<br />
Nup98 and Nup96, which are key controllers of<br />
nuclear entry and exit of proteins and RNAs. The<br />
Nup98 and Nup96-mediated pathway(s) is<br />
highly regulated by specific signaling pathways<br />
such as interferon (IFN) pathways, is a target of<br />
viral proteins, and is involved in tumorigenesis.<br />
Her laboratory currently is characterizing novel<br />
constituents of this pathway and studying their<br />
regulation by signaling pathways, viruses, and<br />
during mitosis. The researchers’ goal is to understand<br />
the molecular mechanisms of the nuclear<br />
transport machinery and how they are regulated<br />
by different signaling pathways and viruses. Thus,<br />
Dr. Fontoura’s research proposes innovative findings<br />
on Nup function and regulation, which are<br />
important to advance the nuclear transport field<br />
and essential for understanding the role of Nups<br />
in cancer and in IFN-mediated processes, such as<br />
anti-viral response, innate immunity, and cell<br />
proliferation.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Enninga, J, Levy, DE, Blobel, G, and Fontoura,<br />
BM. Role of nucleoporin induction in releasing<br />
an mRNA nuclear export block. Science<br />
295:1523-5, 2002.<br />
Comment on the Science publication by<br />
Enninga, J, Levy, DE, Blobel, G, and Fontoura,<br />
BM. Nature Cell Biology 4:E55, 2002.<br />
2003<br />
Yin, X, Fontoura, BM, Morimoto, T, and<br />
Carroll, RB. Cytoplasmic complex of p53 and<br />
eEF2. Journal of Cellular Physiology 196:474-82,<br />
2003.<br />
Enninga, J, Levay, A, and Fontoura, BM. Sec13<br />
shuttles between the nucleus and the cytoplasm<br />
and stably interacts with Nup96 at the nuclear<br />
pore complex. Molecular and Cellular Biology<br />
23:7271-7284, 2003.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Discovered in 2002 that two major NPC proteins<br />
that Dr. Fontoura’s laboratory had previously<br />
identified, Nup98 and Nup96, can<br />
regulate antiviral response by controlling<br />
nuclear export of mRNA. These findings were<br />
published in Science and a comment was published<br />
in Nature Cell Biology. This pathway is<br />
involved in tumorigenesis.<br />
• Discovered in 2003 another constituent of the<br />
Nup98-Nup96 pathway(s), Sec13, which also is<br />
a component of the endoplasmic reticulum.<br />
The findings were recently published in Molecular<br />
and Cellular Biology. Sec13 may be involved<br />
in a crosstalk between the NPC and the endoplasmic<br />
reticulum.<br />
EDWARD W. HARHAJ, PH. D.<br />
Assistant Professor of Microbiology and<br />
Immunology<br />
DESCRIPTION OF RESEARCH<br />
Dr. Harhaj’s research interests focus on the<br />
mechanisms of viral-induced malignancy by<br />
the human T-cell leukemia virus type I (HTLV-<br />
I). HTLV-I is linked to the genesis of both adult<br />
T-cell leukemia (ATL) and a neurological disorder<br />
known as HTLV-I-associated myelopathy/<br />
tropical spastic paraparesis (HAM/TSP). Although<br />
it is unclear why HTLV-I infection proceeds<br />
to either ATL, HAM/TSP, or an<br />
asymptomatic state, there are likely cellular, viral,<br />
and environmental determinants that influence<br />
disease progression. The host immune response<br />
to HTLV-I appears to be an important cellular<br />
determinant of HTLV-I-associated disease.<br />
Whereas ATL patients are commonly immunosuppressed,<br />
asymptomatics and particularly<br />
HAM/TSP patients mount vigorous immune<br />
responses to HTLV-I. One of the goals of the<br />
laboratory is to define the molecular mechanisms<br />
that account for dysregulated host immune responses<br />
to HTLV-I. Understanding how HTLV-I<br />
influences the host immune response may pro-<br />
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vide targets for therapeutic intervention to control<br />
infection and decrease proviral load.<br />
HTLV-I encodes a trans-activating protein,<br />
Tax, which is responsible for the oncogenic properties<br />
of HTLV-I. Tax activates numerous cellular<br />
signaling cascades, including NF-κB and CREB/<br />
ATF, resulting in global changes in gene expression.<br />
Tax regulates the expression of a multitude<br />
of cellular genes that control T-cell activation,<br />
proliferation and apoptosis. Another goal of Dr.<br />
Harhaj’s laboratory is to delineate the mechanisms<br />
utilized by Tax to activate cellular signaling<br />
pathways, such as NF-κB, which are essential for<br />
Tax-mediated immortalization of T cells. Toward<br />
this end, identification of cellular proteins that<br />
interact with Tax may shed light on strategies<br />
used by Tax to constitutively activate NF-κB and<br />
mediate T-cell oncogenesis.<br />
SELECTED PUBLICATIONS<br />
2003<br />
Barmak, K, Harhaj, EW, and Wigdahl, B. Mediators<br />
of central nervous system damage during<br />
the progression of HTLV-I-associated myelopathy/tropical<br />
spastic paraparesis. Journal of<br />
NeuroVirology 9:522-9, 2003.<br />
Barmak, K, Harhaj, EW Grant, C, Alefantis, T,<br />
and Wigdahl, B. Human T cell leukemia virus<br />
type I-induced disease: pathways to cancer and<br />
neurodegeneration. Virology 308:1-12, 2003.<br />
Alefantis, T, Barmak, K, Harhaj, EW, Grant, C,<br />
and Wigdahl, B. Characterization of a nuclear<br />
export signal within the human T cell leukemia<br />
virus type I transactivator protein Tax. Journal of<br />
Biological Chemistry 278:21814-22, 2003.<br />
WILLIAM J. HARRINGTON, JR., M.D.<br />
Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. Harrington's laboratory efforts center on<br />
understanding the mechanisms of antiviralmediated<br />
apoptosis of viral-mediated malignancies.<br />
His team found that interferon (IFN) potently<br />
induces death receptor ligands in certain unique<br />
viral-mediated lymphomas. This had led to a<br />
novel therapeutic approach for these deadly tumors.<br />
Epstein-Barr virus (EBV)-related Burkitts<br />
(BL) and primary central nervous system (CNS)<br />
lymphoma, human herpes virus-type 8 (HHV-8)-<br />
associated primary effusion lymphoma (PEL),<br />
and human T lymphotropic virus-type I (HTLV-<br />
I)-associated adult T-cell leukemia (ATL) are all<br />
refractory to conventional chemotherapy yet remarkably<br />
sensitive to antiviral therapy. Clinical<br />
trials have been designed and implemented that<br />
exploit this phenomenon. Their AIDS-related<br />
brain lymphoma study is now a national trial and<br />
is run through the NCI cooperative group, the<br />
Aids Malignancy Consortium (AMC).<br />
The three principal projects currently underway<br />
include:<br />
• Mapping the apoptotic pathways induced in<br />
viral-associated lymphomas. Their work has<br />
demonstrated that IFNα induced the soluble<br />
death receptor ligand TRAIL, which when<br />
combined with AZT, indicates a FADD-dependent<br />
suicide program in gamma herpes virus<br />
lymphomas. Signal transduction deficits in<br />
IFNα and pathways in resistant tumors also are<br />
being studied.<br />
• Studying the signaling components involved in<br />
constitutive activation of NF-κB in all forms of<br />
viral-mediated non-Hodgkin's lymphoma<br />
(NHL). Their data demonstrate specific activation<br />
pathways that may serve as targets for future<br />
therapeutic agents.<br />
• Elucidating the mechanism whereby AZT<br />
inhibits NF-κB in EBV+ endemic BL. New<br />
data demonstrate that this mechanism is highly<br />
specific and occurs through interruption of<br />
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lymphotoxin beta-mediated activation of<br />
NF-kB. AZT appears to be a targeted form of<br />
therapy particularly active in type 1 latency BL<br />
cells. Dr. Harrington recently has received NCI<br />
funding to study this mechanism in primary<br />
endemic BL cells from patients seen at the National<br />
<strong>Cancer</strong> Institute of Brazil (INCA). This<br />
also will be translated to a clinical trial for refractory<br />
EBV+ B1. They have received a major<br />
commitment from GlaxoSmithKline to provide<br />
parenteral AZT. This will be used as part of a<br />
protocol to treat patients at the INCA.<br />
SELECTED PUBLICATIONS<br />
2002<br />
Tulpule, A, Groopman, J, Saville, MW,<br />
Harrington, WJ Jr , Friedman-Kien, A, Espina,<br />
BM, Garces, C, Mantelle, L, Mettinger, K,<br />
Scadden, DT, and Gill, PS. Multicenter trial of<br />
low-dose paclitaxel in patients with advanced<br />
AIDS-related Kaposi sarcoma. <strong>Cancer</strong> 95:147-<br />
54, 2002.<br />
2003<br />
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,<br />
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,<br />
Cabral, L, Barber, GN, and Harrington, WJ Jr .<br />
Potentiation of TRAIL-induced apoptosis in<br />
primary effusion lymphoma through<br />
azidothymidine-mediated inhibition of NFkappa<br />
B. Blood 101:2321-7, 2003.<br />
Rosenblatt, J and Harrington, WJ Jr . Leukemia<br />
and myelopathy: the persistent mystery of pathogenesis<br />
by HTLV-I/II. <strong>Cancer</strong> Investigation<br />
21:323-4, 2003.<br />
Schultz, DR and Harrington, WJ Jr . Apoptosis:<br />
programmed cell death at a molecular level.<br />
Seminars in Arthritis and Rheumatism 32:345-<br />
69, 2003.<br />
ANTERO G. SO, M.D., PH.D.<br />
Professor of Medicine<br />
DESCRIPTION OF RESEARCH<br />
Dr. So and Kathleen M. Downey, Ph.D., are<br />
studying the molecular mechanism by which<br />
normal cells regulate proliferation during the cell<br />
cycle and how this is altered in cancer cells. The<br />
major focus of these studies is DNA polymerase<br />
delta, the principal mammalian DNA polymerase<br />
required for replication of chromosomal DNA<br />
and involved in several major DNA repair pathways.<br />
DNA polymerase delta was the first eukaryotic<br />
DNA polymerase found to have an intrinsic<br />
proofreading 3’ to 5’ exonuclease activity and<br />
therefore capable of editing errors made during<br />
DNA synthesis. The importance of this proofreading<br />
activity in DNA replication was recently<br />
shown by a report that inactivation of the exonuclease<br />
activity of DNA polymerase delta in mice<br />
resulted in a recessive mutator phenotype characterized<br />
by a high incidence of epithelial (carcinoma)<br />
and mesenchymal (lymphomas and<br />
sarcomas) cancers. Current research emphasizes<br />
the elucidation of the molecular mechanism of<br />
regulation of DNA polymerase delta activity by<br />
its processivity factor, the proliferating cell<br />
nuclear antigen (PCNA), and the identification<br />
of new proteins that regulate DNA polymerase<br />
delta activity.<br />
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SELECTED PUBLICATIONS<br />
2002<br />
Carastro, LM, Tan, CK, Selg, M, Jack, HM, So,<br />
AG, and Downey, KM. Identification of delta<br />
helicase as the bovine homolog of HUPF1: demonstration<br />
of an interaction with the third subunit<br />
of DNA polymerase delta. Nucleic Acids<br />
Research 30:2232-43, 2002.<br />
Meyer, PR, Matsuura, SE, Tolun, AA, Pfeifer, I,<br />
So, AG, Mellors, JW, and Scott, WA. Effects of<br />
specific zidovudine resistance mutations and substrate<br />
structure on nucleotide-dependent primer<br />
unblocking by human immunodeficiency virus<br />
type 1 reverse transcriptase. Antimicrobial Agents<br />
and Chemotherapy 46:1540-5, 2002.<br />
Lu, X, Tan, CK, Zhou, JQ, You, M, Carastro,<br />
LM, Downey, KM, and So, AG. Direct interaction<br />
of proliferating cell nuclear antigen with the<br />
small subunit of DNA polymerase delta. Journal<br />
of Biological Chemistry 277:24340-5, 2002.<br />
HIGHLIGHTS/DISCOVERIES<br />
• Demonstrated a direct interaction between the<br />
small subunit of human DNA polymerase delta<br />
(p50) and PCNA, a marker for cell proliferation,<br />
by reciprocal co-immunoprecipitation of<br />
the two proteins using antibodies against either<br />
p50 or PCNA, suggesting that this interaction<br />
is primarily responsible for processive DNA<br />
synthesis by DNA polymerase delta. Researchers<br />
in Dr. So’s laboratory have now confirmed<br />
that this interaction readily occurs in cells. This<br />
is important because the interaction of DNA<br />
polymerase delta with PCNA is at the core of<br />
replication machinery (replisome) function and<br />
crucial to our understanding of how DNA replication<br />
is coordinated with DNA repair and<br />
cell cycle progression.<br />
• Identified a novel 36-kDa protein, designated<br />
polymerase delta interacting protein 1 (PDIP1)<br />
that physically and functionally interacts with<br />
both PCNA and the 50-kDa subunit of DNA<br />
polymerase delta, both in vitro and in vivo.<br />
Researchers further have shown the expression<br />
of this protein is induced by tumor necrosis factor<br />
α (TNF-α) and interleukin-6 (IL-6). These<br />
cytokines are essential for growth and proliferation<br />
of many cell types and implicated in the<br />
tumorigenesis of a number of cancers, including<br />
AIDS-related non-Hodgkin’s lymphoma and<br />
multiple myeloma. Thus, PDIP1 is a potential<br />
target for the development of novel therapeutic<br />
agents for the treatment of these tumors.<br />
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S H A R E D R E S O U R C E S<br />
S H A R E D R E S O U R C E S<br />
A N A L Y T I C A L I M A G I N G C O R E<br />
MANAGER<br />
Alberto Pugliese, M.D.<br />
Associate Professor of Medicine<br />
CO-MANAGER<br />
Beata R. Frydel, Ph.D.<br />
Associate Scientist of Neurosurgery<br />
PURPOSE<br />
Many research endeavors rely on state-of-theart<br />
imaging and molecular histology techniques<br />
requiring the use of complex and costly<br />
equipment not practical for the individual investigator<br />
to acquire and maintain. The Analytical<br />
Imaging Core is a campus-wide resource spearheaded<br />
by the Diabetes Research Institute and<br />
UM/<strong>Sylvester</strong>, with seed support from the dean<br />
of the University of Miami School of Medicine.<br />
The Juvenile Diabetes Research Foundation<br />
awarded additional support for a five-year period<br />
in December 2003. The core’s main goals are to:<br />
• Provide access to sophisticated, modern instrumentation<br />
for imaging and molecular analysis<br />
of tissue and cellular specimens to investigators.<br />
• Provide expertise, guidance, and training to<br />
core users and help them optimize protocols for<br />
their applications that can be shared with other<br />
investigators.<br />
SERVICES<br />
This core provides the following services:<br />
1) Confocal Microscopy: Confocal microscopy offers<br />
many advantages over standard fluorescent<br />
microscopy including increased sensitivity,<br />
resolution, and the ability to image relatively<br />
thick, fluorescently labeled biological specimens<br />
in two or three dimensions. Confocal<br />
microscopy creates an “optical section” of the<br />
cells or tissues being imaged and an increase in<br />
effective resolution due to a large increase in<br />
signal-to-noise ratio. As a result, outstanding<br />
images can be collected from cells and tissue<br />
sections that would otherwise yield little or no<br />
information.<br />
The workhorse instrument for confocal microscopy<br />
is the Zeiss LSM-510, which can detect<br />
up to five channels and four fluorescent<br />
channels simultaneously—from UV to far red,<br />
plus a separate detector for transmitted light.<br />
The outstanding beam control afforded by the<br />
Zeiss LSM-510 makes it an ideal instrument<br />
for other advanced fluorescent applications<br />
such as fluorescence resonance energy transfer<br />
(FRET), fluorescence recovery after photo<br />
bleaching (FRAP), or ratio-imaging for<br />
fluorescence quantitation. The core also is<br />
equipped with an Atto Instruments spinning<br />
disk confocal microscope (CARV), a confocal<br />
instrument particularly suited for live cell<br />
analysis, and video-rate (30 frames per second)<br />
imaging.<br />
2) Standard Epifluorescence Microscopy: The core<br />
also is equipped with a Leica DMIRB inverted<br />
microscope capable of performing triple fluorescence,<br />
phase contrast, and light microscopy, etc.<br />
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3) Laser Scanning Cytometer (LSC): The LSC allows<br />
“flow cytometer-like” fluorescent imaging<br />
and quantitation of tissue sections on a microscope<br />
slide. The LSC records the position and<br />
time of measurement for each cell analyzed so<br />
that multiple biochemical, immunological,<br />
and morphological measurements can be made<br />
on each cell. Possible applications for the LSC<br />
include: detection and quantitation of<br />
apoptosis (TUNEL, annexin); in situ hybridization<br />
(FISH); and the study of cell adhesion,<br />
cell cycle, and DNA content, etc.<br />
4) MetaMorph Imaging System (MIS): This imaging<br />
system consists of hardware and software<br />
that enables the capture and analysis of microscopy<br />
and digital images obtained using the<br />
instruments described above.<br />
5) Laser Capture Dissection Microscope (LCM):<br />
The LCM can dissect portions of tissues (or<br />
even single cells) from cell smears and fixed<br />
and frozen tissue sections, obtaining essentially<br />
pure samples of a desired cell population (500-<br />
1,000 cells per hour). The dissected cells can<br />
then be used to extract RNA, DNA, or proteins<br />
for further studies. LCM offers unprecedented<br />
access to specific cells for defining<br />
their pattern of gene expression, in combination<br />
with powerful techniques such as gene<br />
array and real-time PCR. This technology is<br />
particularly powerful in the study of human<br />
diseases and several cancer applications, where<br />
only small amounts of tissue may be available<br />
for study.<br />
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S H A R E D R E S O U R C E S<br />
B I O S T A T I S T I C S<br />
MANAGER<br />
James J. Schlesselman, Ph.D.<br />
Professor of Epidemiology and Public Health<br />
PURPOSE<br />
The division of Biostatistics provides statistical<br />
expertise in the study, design, and analysis<br />
of data for UM/<strong>Sylvester</strong> members. Statisticians<br />
collaborate on developing protocols for clinical<br />
trials, work together on research proposals for<br />
laboratory-based investigations, and conduct epidemiological<br />
studies. They also perform statistical<br />
analyses, interpret results, and author or coauthor<br />
papers for publication. Biostatistics is<br />
committed to applying statistical and computational<br />
methods to improve the way in which<br />
clinical trials and translational research are conducted<br />
within UM/<strong>Sylvester</strong> and to developing<br />
statistical methodology that aids cancer research.<br />
SERVICES<br />
Biostatistics provides cancer center members with<br />
the following services:<br />
1) Collaboration: Biostatistics seeks to establish<br />
enduring collaborations with UM/<strong>Sylvester</strong><br />
investigators to advance the cancer center’s<br />
programmatic research. Such collaborations<br />
develop statisticians’ knowledge of specific areas<br />
of cancer-related investigation and ensure<br />
that statistical considerations are adequately<br />
incorporated throughout the course of ongoing<br />
research programs. Priority is given to collaborative<br />
work, not consulting.<br />
2) Consulting: In contrast to collaborations,<br />
which involve long-term collegial relationships<br />
in planning studies or analyzing data, statistical<br />
consulting generally entails statistical advice<br />
or analysis with little involvement in the<br />
studies themselves and no co-authorship of<br />
publications. Consulting, however, is sometimes<br />
a preliminary step to collaborative research<br />
where Biostatistics plays a significant<br />
role.<br />
3) Study Design: Biostatistics formulates study<br />
objectives and endpoints in terms that are appropriate<br />
for statistical analysis, recommends<br />
alternative study designs, determines the<br />
sample size needed to address study objectives<br />
at an appropriate level of significance and<br />
power, and develops and writes plans for statistical<br />
analyses.<br />
4) Data Analysis: After study data have been collected,<br />
biostatisticians provide graphical and<br />
tabular reports of the results as well as substantive<br />
interpretation of the findings.<br />
5) Clinical Trial Applications: Biostatisticians contribute<br />
to the design and statistical analysis of<br />
investigator-initiated phase I and phase II cancer<br />
clinical trials; clinical epidemiology studies;<br />
novel diagnostic tests; clinical investigations of<br />
cancer therapies; basic science studies of cancer<br />
mechanisms; and translational studies of immunologic<br />
therapies, chemotherapy-modifying<br />
agents, and radio-sensitizing drugs.<br />
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S H A R E D R E S O U R C E S<br />
C E L L P U R I F I C A T I O N A N D B A N K I N G F A C I L I T Y<br />
MANAGER<br />
Kelvin P. Lee, M.D.<br />
Associate Professor of Microbiology and<br />
Immunology<br />
PURPOSE<br />
For many UM/<strong>Sylvester</strong> researchers, the transition<br />
from small animal to human studies is<br />
prevented by their inability to obtain primary<br />
human cells, whether normal or malignant. The<br />
overall goal of this facility is to generate purified<br />
primary human cells for the cancer research community<br />
at the University of Miami.<br />
SERVICES<br />
Specifically, the services of this facility are to:<br />
1) Provide purified normal primary human hematopoietic<br />
cells (T cells, B cells, monocytes,<br />
and CD34+ stem cells) for cancer-related<br />
research.<br />
2) Bank and provide primary leukemia, lymphoma,<br />
and myeloma cell isolates to investigators<br />
working with these malignancies.<br />
3) Provide centralized hematopoietic cell isolation,<br />
banking, inventory, and database capability<br />
for cancer-related clinical trials that are<br />
collecting cell samples for research.<br />
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S H A R E D R E S O U R C E S<br />
C L I N I C A L R E S E A R C H S E R V I C E S R E S O U R C E<br />
CLINICAL DIRECTOR<br />
Joseph A. Lucci, III., M.D.<br />
Associate Professor of Obstetrics and<br />
Gynecology<br />
ASSISTANT DIRECTOR<br />
James D. Hanlon, Jr., R.N.<br />
Manager<br />
PURPOSE<br />
The Clinical Research Services Resource<br />
provides UM/<strong>Sylvester</strong> investigators with<br />
broad-based support for their clinical research<br />
activities to:<br />
• Evaluate clinical trial protocol design, scientific<br />
merit, and patient care-related issues through<br />
the UM/<strong>Sylvester</strong> Protocol Review Committee.<br />
• Provide support services for screening, evaluating,<br />
recruiting, tracking, protecting, and maintaining<br />
patients on clinical protocols.<br />
• Assist investigators with protocol development<br />
by providing consultation in protocol design,<br />
access to other needed resources, and assistance<br />
with reporting requirements and other federal<br />
regulations.<br />
• Assure compliance with guidelines for investigational<br />
drug use and toxicity reporting and<br />
maintain quality data management.<br />
• Develop a data safety and monitoring board to<br />
monitor institutional clinical trials.<br />
• Support national cooperative group activities<br />
and interact with UM/<strong>Sylvester</strong> affiliates.<br />
• Develop, operate, and maintain a computerized<br />
protocol data management system.<br />
• Budget clinical trial expenditures and negotiate<br />
contracts with clinical trial sponsors.<br />
SERVICES<br />
1) Regulatory Office: This office handles all activities<br />
involving activation of clinical trials, which<br />
include preparing and presenting documents<br />
to both the Protocol Review Committee<br />
and the University of Miami Internal Review<br />
Board, writing informed consents, and distributing<br />
active protocols throughout the clinical<br />
areas on the medical campus.<br />
2) Informatics Office: This office maintains the<br />
database for institutional trials, monitors the<br />
charge-back system, provides lists of active<br />
clinical trials, and assists with quality control<br />
procedures.<br />
3) Budget Office: This office controls the budget<br />
for the Clinical Research Services Resource’s<br />
personal and office expenditures and negotiates<br />
contracts with clinical trial sponsors.<br />
4) Quality Assurance: This office monitors the<br />
quality of data management and conducts case<br />
auditing to ensure compliance with FDA requirements.<br />
It also interacts with the Data<br />
Safety and Monitoring Board.<br />
5) Research Pharmacy: The research pharmacy is<br />
responsible for investigational drug accountability<br />
and inventory, as well as providing drug<br />
information for medical, nursing, and pharmacy<br />
staff.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 147
S H A R E D R E S O U R C E S<br />
D N A C O R E F A C I L I T Y<br />
MANAGER<br />
Rudolf K. Werner, Ph.D.<br />
Professor of Biochemistry and Molecular<br />
Biology<br />
PURPOSE<br />
The purpose of the DNA Core Facility is to<br />
make DNA sequencing services available to<br />
UM/<strong>Sylvester</strong> members in support of their peerreviewed<br />
funded research.<br />
SERVICES<br />
This facility provides cancer center investigators<br />
with the following services:<br />
1) DNA Sequencing: The investigator provides<br />
purified DNA for analysis and receives a sequence<br />
within three to five days. The sequence<br />
data are about 98 percent accurate. Some investigators<br />
perform their own sequencing reactions<br />
and provide the completed reaction<br />
mixture for analysis on the instrument.<br />
To achieve more uniform DNA quality, the<br />
facility also offers, for a small surcharge, DNA<br />
purification from a single bacterial colony<br />
containing the plasmid to be sequenced.<br />
In addition to the sequence analysis of doublestranded<br />
DNA, the facility also provides<br />
sequencing of polymerase chain reaction<br />
(PCR) products. These results are usually<br />
superior to those obtained from cloning DNA.<br />
2) Order Coordination: The facility coordinates<br />
orders for the synthesis of oligonucleotides<br />
from commercial sources.<br />
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S H A R E D R E S O U R C E S<br />
F L O W C Y T O M E T R Y R E S O U R C E<br />
MANAGER<br />
Richard L. Riley, Ph.D.<br />
Professor of Microbiology and Immunology<br />
PURPOSE<br />
The Flow Cytometry Resource provides<br />
UM/<strong>Sylvester</strong> investigators, in support of<br />
their peer-reviewed funded research, with sophisticated<br />
methods for analysis and preparative<br />
sorting of normal and tumor cells, and trains<br />
investigators in the use of flow cytometry for<br />
their research.<br />
SERVICES<br />
This resource provides the following services to<br />
cancer center members:<br />
1) Laser-excited flow cytometry for analysis of<br />
cell surface antigens expressed in complex cell<br />
mixtures; up to four different fluorescent<br />
parameters and two light-scatter parameters<br />
(forward and side scatter) can be analyzed<br />
simultaneously.<br />
2) Laser-excited cell sorting (six parameters) for<br />
isolation of selected cell populations from<br />
heterogeneous mixtures.<br />
3) DNA content/cell cycle analysis via both<br />
visibly excited dyes (propidium iodide) and<br />
UV-excited dyes (Hoescht dyes) with pulse<br />
processing or doublet discrimination.<br />
4) High-efficiency sorting and sorting of large<br />
particles via the MacroSort system.<br />
5) Intracellular calcium ratio measurements.<br />
6) Applications for limiting dilution or cloning<br />
experiments via the automatic cell deposition<br />
unit (ACDU).<br />
7) Training in the use of the FACScan and LSR<br />
analytical flow cytometers, computer programs<br />
for data analysis, and data storage; consultation<br />
in the procedures for cell preparation,<br />
staining, fixation, data analysis, and preparative<br />
sorting also are provided.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 149
S H A R E D R E S O U R C E S<br />
G E N E K N O C K O U T A N D T R A N S G E N E F A C I L I T Y<br />
MANAGER<br />
Thomas R. Malek, Ph.D.<br />
Professor and Vice Chair of Microbiology<br />
and Immunology<br />
PURPOSE<br />
The Gene Knockout and Transgene Facility<br />
produces transgenic and knockout mice and<br />
trains investigators to apply this technology to<br />
their research. The major goal of the facility is to<br />
provide this technological capability to peer-reviewed<br />
funded cancer researchers at UM/<br />
<strong>Sylvester</strong>.<br />
SERVICES<br />
This facility provides the following services to<br />
cancer center members:<br />
1) Set up breeding of donor and recipient mice<br />
and subsequently check plugs to confirm<br />
mating.<br />
2) Perform vasectomies of male mice for the<br />
recipient colony.<br />
3) Collect fertilized eggs or blastocysts.<br />
4) Sort and culture eggs.<br />
5) Prepare microinjection needles.<br />
6) Microinject eggs with DNA or blastocysts<br />
with cells.<br />
7) Inject donor and recipient mice with<br />
hormones.<br />
8) Perform microsurgery to re-implant eggs or<br />
blastocysts.<br />
9) Culture and transfer embryonic stem cells for<br />
microinjection into blastocysts.<br />
10) Generate gene-targeting constructs rapidly<br />
by using an arrayed library.<br />
11) Provide investigators with tissue biopsies to<br />
screen for transmission of transgene.<br />
12) Advise investigators in the production of<br />
transgenic and gene knockout constructs.<br />
13) Advise investigators in culturing and gene<br />
targeting in embryonic stem cells.<br />
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S H A R E D R E S O U R C E S<br />
H I S T O L O G Y R E S E A R C H L A B C O R E<br />
MANAGER<br />
Carol K. Petito, M.D.<br />
Professor of Pathology<br />
PURPOSE<br />
The UM/<strong>Sylvester</strong> Histology Research Lab<br />
Core provides histology services to cancer<br />
center members in support of their peer-reviewed<br />
funded research and of their preliminary studies<br />
completed to prepare for grant submission.<br />
SERVICES<br />
The facility currently provides the following services:<br />
1) Processing of fixed material into paraffin<br />
blocks.<br />
2) Tissue sectioning for routine hematoxylineosin<br />
stains and other stains.<br />
3) Tissue sectioning for immunohistochemistry.<br />
4) Professional consulting for methodology and<br />
for histological interpretation.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 151
S H A R E D R E S O U R C E S<br />
I N F O R M A T I C S<br />
ASSOCIATE DIRECTOR<br />
Dido Franceschi, M.D.<br />
Associate Professor of Surgery<br />
PURPOSE<br />
The Division of Informatics at UM/<strong>Sylvester</strong><br />
facilitates the integration of information to<br />
support patient care, research, education, and<br />
administration. The division is composed of<br />
two subdivisions: Systems Development and<br />
Support and Network Management and Personal<br />
Computing.<br />
SERVICES<br />
Systems Development and Support<br />
The Systems Development team conducts<br />
technical research and development to meet<br />
UM/<strong>Sylvester</strong>’s short- and long-term requirements.<br />
It also delivers software solutions in<br />
the areas of research, administration, and web<br />
development. The team’s primary objective is<br />
to increase productivity and efficiency in various<br />
areas of the cancer center by providing:<br />
1) Systems analysis and design services.<br />
2) Database development, administration, and<br />
support.<br />
3) Programming of quality computer applications.<br />
4) Development of Intranet web sites that provide<br />
employees with organized, readily accessible<br />
information in a central repository and<br />
secured web-based applications.<br />
5) Project management and implementation,<br />
which includes technical and user documentation<br />
and user training.<br />
6) Expedited document processing via electronic<br />
forms that are accessible through the web.<br />
The group provides infrastructure support with<br />
web-enabled database systems as follows:<br />
Research: The essential support needed by<br />
UM/<strong>Sylvester</strong> investigators is provided by the<br />
Systems Development team for the management<br />
of clinical trials and the protocol approval process;<br />
tracking of patient accrual data; collection of research<br />
personnel time and generation of invoices<br />
for protocol billing; management of investigatorinitiated<br />
clinical trial patient data; administration<br />
of web accessible protocols and related documents;<br />
secure dissemination of reports to investigators;<br />
and management of patient tissue banks<br />
including a web interface that allows investigators<br />
to search the tissue bank and request specimens<br />
according to their investigational interests.<br />
Administration: A centralized database system has<br />
been developed that unifies information from the<br />
various administrative divisions and facilitates the<br />
management and sharing of information. The<br />
database and related applications provide functionality<br />
for the management of UM/<strong>Sylvester</strong>’s<br />
members as well as profiles of their research interests<br />
and involvement, investigator’s published<br />
materials, grants, and research funded projects,<br />
shared resource facilities, and human resources.<br />
Network Management and Personal<br />
Computing<br />
The Network Management team provides infrastructure<br />
support for cancer center connectivity,<br />
central computing hardware, and firewall security.<br />
The network group has four major functions:<br />
1) Integrate information systems and communications<br />
for the research, administrative, and<br />
clinical areas of the cancer center.<br />
2) Support the operation of a center-wide<br />
Intranet with defined security.<br />
3) Support connectivity to campus networks<br />
including access to wide-area networks.<br />
4) Assist with hardware and software installation<br />
and support.<br />
5) Provide system backup, disaster recovery, and<br />
high availability.<br />
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S H A R E D R E S O U R C E S<br />
M O L E C U L A R A N A L Y S I S C O R E<br />
MANAGER<br />
Roland Jurecic, Ph.D.<br />
Assistant Professor of Microbiology and<br />
Immunology<br />
PURPOSE<br />
The Molecular Analysis Core provides UM/<strong>Sylvester</strong><br />
members with: 1) capillary-based DNA<br />
sequencing of plasmids and polymerase chain<br />
reaction (PCR) fragments, 2) shotgun sequencing<br />
of large cDNA and genomic DNA inserts<br />
(transgenic and knockout/targeting vectors), 3)<br />
basic DNA fragment analysis, and 4) real time<br />
quantitative PCR and reverse transcriptase-PCR<br />
(RT-PCR) using LightCycler technology.<br />
3) Basic DNA fragment analysis. Detection of<br />
isoforms, alternative transcripts, and DNA rearrangements,<br />
etc.<br />
4) Automated heterozygote detection.<br />
Quantitative Real Time PCR Techniques Using<br />
the Roche LightCycler<br />
1) Real time quantitative PCR and RT-PCR.<br />
2) Full melt curve analysis of amplified products.<br />
3) Design and testing of fluorogenic probes for<br />
rapid and sensitive detection of gene targets.<br />
4) Genotyping of transgenic and knockout<br />
mouse models.<br />
SERVICES<br />
This facility provides UM/<strong>Sylvester</strong> investigators,<br />
in support of their peer-reviewed research, with<br />
the following services:<br />
Genetic Analysis using the Beckman CEQ 2000<br />
Genetic Analyzer<br />
1) Capillary-based DNA sequencing of plasmids<br />
and PCR fragments (800 base pairs in 90 minutes),<br />
using standard (T3, T7, Sp6, M13, etc.)<br />
or custom-designed primers.<br />
2) Shotgun sequencing of large cDNA and genomic<br />
DNA inserts (transgenic and knockout/targeting<br />
vectors) using transposon technology for<br />
fast and easy insertion of sequencing primer<br />
binding sites and kanamycin resistance markers<br />
into target DNA in vitro. Selection of different<br />
clones with transposon integrated only<br />
into the genomic insert (not the plasmid<br />
backbone) by digest restriction and size difference.<br />
Based on the insert size, 20 to 40 different<br />
clones are subjected to automated sequencing<br />
and assembled into contigs using sequence utility<br />
software.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong> 153
S H A R E D R E S O U R C E S<br />
P O P U L A T I O N R E S E A R C H C O R E<br />
(Developing Shared Resource)<br />
DIRECTOR<br />
Michael H. Antoni, Ph.D.<br />
Professor of Psychology<br />
MANAGER<br />
Dorothy F. Parker, M.H.S.<br />
PURPOSE<br />
The purpose of the Population Research Core<br />
will be to provide services to support population-based<br />
cancer prevention and control research<br />
at UM/<strong>Sylvester</strong> and to help increase the diversity<br />
of study participants to represent the racial, ethnic,<br />
and socioeconomic composition of South<br />
Florida’s diverse and unique community.<br />
The Population Research Core evolved from<br />
the Florida <strong>Comprehensive</strong> <strong>Cancer</strong> Control Initiative<br />
(FCCCI), a project funded by the <strong>Center</strong>s<br />
for Disease Control that established regional cancer<br />
control collaboratives throughout Florida.<br />
UM/<strong>Sylvester</strong> continues to support the Southeast<br />
Florida Regional <strong>Cancer</strong> Control Collaborative, a<br />
group of more than 40 organizations that are a<br />
potential source of recruitment for populationbased<br />
studies. FCCCI’s staff of three also supports<br />
the Population Research Core. They have<br />
experience in cancer control research, data analysis,<br />
and community outreach.<br />
SERVICES<br />
The Population Research Core will offer services<br />
in three areas: recruitment, data and measurement,<br />
and education. Additionally, in an effort to<br />
better meet the needs of UM/<strong>Sylvester</strong> investigators,<br />
the core is conducting a faculty survey to<br />
determine what is needed to facilitate research<br />
and recruitment.<br />
Recruitment<br />
1) Help UM/<strong>Sylvester</strong> investigators develop and<br />
assess recruitment and retention plans for<br />
funded projects.<br />
2) Increase awareness of population research<br />
studies open for accrual.<br />
3) Serve as liaison with local health care providers<br />
and community organizations.<br />
4) Develop agreements and procedures for recruitment<br />
of participants in cancer control<br />
studies.<br />
5) Pretest and/or conduct focus groups with target<br />
populations to develop appropriate recruitment<br />
tools and strategies (e.g., brochures,<br />
flyers, and advertisements).<br />
Data and Measurement<br />
1) Provide aggregate local, regional, and national<br />
cancer and demographic data.<br />
2) Help develop or identify appropriate questionnaires<br />
and survey tools.<br />
3) Arrange for translation of materials (e.g., into<br />
Spanish and Haitian Creole).<br />
4) Provide assistance with data collection tools<br />
and database design.<br />
Education<br />
1) Assess needs of investigators for understanding<br />
issues related to population science.<br />
2) Provide workshops and training on issues such<br />
as: community outreach and campus-community<br />
research concerns, cultural and socioeconomic<br />
factors that affect recruitment<br />
strategies, study design, the informed consent<br />
process, and participation in studies.<br />
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P U B L I C A T I O N S 2 0 0 2 - 2 0 0 3<br />
P U B L I C A T I O N S 2 0 0 2 - 2 0 0 3<br />
Muller-Sieburg, CE, Cho, RH, Thoman, M,<br />
Adkins, B, and Sieburg, HB. Deterministic regulation<br />
of hematopoietic stem cell self-renewal and<br />
differentiation. Blood 100:1302-9, 2002.<br />
Adkins, B, Bu, Y, and Guevara, P. Murine neonatal<br />
CD4+ lymph node cells are highly deficient in<br />
the development of antigen-specific Th1 function<br />
in adoptive adult hosts. Journal of Immunology<br />
169:4998-5004, 2002.<br />
Lopez, DM, Charyulu, V, and Adkins, B. Influence<br />
of breast cancer on thymic function in mice.<br />
Journal of Mammary Gland Biology and Neoplasia<br />
7:191-9, 2002.<br />
Petito, CK, Adkins, B, McCarthy, M, Roberts, B,<br />
and Khamis, I. CD4+ and CD8+ cells accumulate<br />
in the brains of acquired immunodeficiency<br />
syndrome patients with human immunodeficiency<br />
virus encephalitis. Journal of<br />
Neurovirology 9:36-44, 2003.<br />
Adkins, B, Williamson, T, Guevara, P, and Bu, Y.<br />
Murine neonatal lymphocytes show rapid early<br />
cell cycle entry and cell division. Journal of Immunology<br />
170:4548-56, 2003.<br />
Auais, A, Adkins, B, Napchan, G, and<br />
Piedimonte, G. Immunomodulatory effects of<br />
sensory nerves during respiratory syncytial virus<br />
infection in rats. American Journal of Physiology-<br />
Lung Cellular and Molecular Physiology<br />
285:L105-13, 2003.<br />
Adkins, B, Bu, Y, Vincek, V, and Guevara, P.<br />
The primary responses of murine neonatal lymph<br />
node CD4 + cells are Th2-skewed and are sufficient<br />
for the development of Th2-biased memory.<br />
Clinical & Developmental Immunology 10:43-<br />
51, 2003.<br />
Adkins, B. Peripheral CD4 + lymphocytes derived<br />
from fetal versus adult thymic precursors differ<br />
phenotypically and functionally. Journal of Immunology<br />
171:5157, 2003.<br />
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,<br />
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,<br />
Schneiderman, N, and Fletcher, MA. Stress<br />
management and immune system reconstitution<br />
in symptomatic HIV-infected gay men over<br />
time: effects on transitional naive T cells<br />
(CD4(+)CD45RA(+)CD29(+)). American<br />
Journal of Psychiatry 159:143-45, 2002.<br />
Knippels, HM, Goodkin, K, Weiss, JJ, Wilkie,<br />
FL, and Antoni, MH. The importance of cognitive<br />
self-report in early HIV-1 infection: validation<br />
of a cognitive functional status subscale.<br />
AIDS 16:259-67, 2002.<br />
Culver, JL, Arena, PL, Antoni, MH, and Carver,<br />
CS. Coping and distress among women under<br />
treatment for early stage breast cancer: comparing<br />
African Americans, Hispanics and non-Hispanic<br />
Whites. Psycho-oncology 11:495-504, 2002.<br />
Cruess, S, Antoni, MH, Hayes, A, Penedo, F,<br />
Ironson, G, Fletcher, MA, Lutgendorf, S, and<br />
Schneiderman, N. Changes in mood and depressive<br />
symptoms and related change processes during<br />
cognitive behavioral stress management in<br />
HIV-infected men. Cognitive Therapy and<br />
Research 26:373-392, 2002.<br />
Kumar, M, Kumar, AM, Waldrop, D, Antoni,<br />
MH, Schneiderman, N, and Eisdorfer, C.<br />
The HPA axis in HIV-1 infection. Journal of<br />
Acquired Immune Deficiency Syndromes 31<br />
Supplement 2:S89-93, 2002.<br />
Antoni, MH. Stress management and<br />
psychoneuroimmunology in HIV infection.<br />
CNS Spectrums 8:40-51, 2003.<br />
Perna, FM, Antoni, MH, Baum, A, Gordon, P,<br />
and Schneiderman, N. Cognitive behavioral<br />
stress management effects on injury and illness<br />
among competitive athletes: a randomized<br />
clinical trial. Annals of Behavioral Medicine<br />
25:66-73, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong><br />
155
P U B L I C A T I O N S 2 0 0 2 - 2 0 0 3<br />
Antoni, MH. Psychoneuroendocrinology and<br />
psychoneuroimmunology of cancer: Plausible<br />
mechanisms worth pursuing? Brain, Behavior,<br />
and Immunity (1 Supplement):S84-91, 2003.<br />
Antoni, MH and Pitts, M. Journal of Psychosomatic<br />
Research, Special Issue. Journal of Psychosomatic<br />
Research 54:179-83, 2003.<br />
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,<br />
MA, Klimas, N, Duran, R, Ironson, G, and<br />
Schneiderman, N. Sleep disturbance mediates the<br />
association between psychological distress and<br />
immune status among HIV-positive men and<br />
women on combination antiretroviral therapy.<br />
Journal of Psychosomatic Research 54:185-89,<br />
2003.<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, Fletcher, MA, and<br />
O’Sullivan, MJ. Stress as a predictor of symptomatic<br />
genital herpes virus recurrence in women<br />
with human immunodeficiency virus. Journal of<br />
Psychosomatic Research 54:237-44, 2003.<br />
Petronis, VM, Carver, CS, Antoni, MH, and<br />
Weiss, S. Investment in body image and psychosocial<br />
well-being among women treated for early<br />
stage breast cancer: partial replication and extension.<br />
Psychology & Health 18:1-13, 2003.<br />
Pereira, DB, Antoni, MH, Danielson, A, Simon,<br />
T, Efantis-Potter, J, Carver, CS, Duran, RE,<br />
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life<br />
stress and cervical squamous intraepithelial lesions<br />
in women with human papillomavirus and<br />
human immunodeficiency virus. Psychosomatic<br />
Medicine 65:427-34, 2003.<br />
Weiss, JL, Mulder, CL, Antoni, MH, De<br />
Vroome, EM, Garssen, B, and Goodkin, K. Effects<br />
of a supportive-expressive group intervention<br />
on long-term psychosocial adjustment in<br />
HIV-infected gay men. Psychotherapy and Psychosomatics<br />
72:132-40, 2003.<br />
156<br />
McGregor, BA, Antoni, MH, Boyers, A, Alferi,<br />
SM, Blomberg, BB, and Carver, CS. Cognitive<br />
behavioral stress management increases benefit<br />
finding and immune function among women<br />
with early stage breast cancer. Journal of Psychosomatic<br />
Research 54:1- 8, 2003.<br />
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,<br />
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,<br />
and Schneiderman, N. Psychological distress is<br />
associated with decreased memory helper T-cell<br />
and B-cell counts in pre-AIDS HIV seropositive<br />
men and women but only in those with low viral<br />
load. Psychosomatic Medicine 65:627-35, 2003.<br />
O’Cleirigh, C, Ironson, G, Antoni, MH,<br />
Fletcher, MA, McGuffey, L, Balbin, E,<br />
Schneiderman, N, and Solomon, G. Emotional<br />
expression and depth processing of trauma and<br />
their relation to long-term survival in patients<br />
with HIV/AIDS. Journal of Psychosomatic Research<br />
54:225-35, 2003.<br />
Robbins, M, Szapocznik, J, Tejeda, M, Samuels,<br />
D, Ironson, G, and Antoni, MH. The protective<br />
role of the family and social support network in<br />
a sample of HIV+ African American women:<br />
results of a pilot study. Journal of Black Psychology<br />
29:17-37, 2003.<br />
Lechner, SC, Antoni, MH, Lydston, D,<br />
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,<br />
Schneiderman, N, Brondolo, E, Tobin, J, and<br />
Weiss, S. Cognitive-behavioral interventions improve<br />
quality of life in women with AIDS. Journal<br />
of Psychosomatic Research 54: 253-261,<br />
2003.<br />
Lechner, SC, Zakowski, SG, Antoni, MH,<br />
Greenhawt, M, Block, K, and Block, P. Do<br />
sociodemographic and disease-related factors influence<br />
benefit-finding in cancer patients?<br />
Psycho-oncology 12: 491-499, 2003.<br />
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,<br />
Carver, CS, Antoni, MH, Roos, BA, and<br />
Schneiderman, N. Perceived stress management<br />
skill mediates the relationship between optimism<br />
and positive mood following radical prostatectomy.<br />
Health Psychology 22:220-2, 2003.<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
P U B L I C A T I O N S 2 0 0 2 - 2 0 0 3<br />
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni,<br />
MH, Malow, R, Costa, P, and Schneiderman, N.<br />
Personality, quality of life and HAART adherence<br />
among men and women living with HIV/AIDS.<br />
Journal of Psychosomatic Research 54:271-8,<br />
2003.<br />
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,<br />
Antoni, MH, Ironson, G, Malow, R, and<br />
Schneiderman, N. Coping and psychological distress<br />
among symptomatic HIV+ men who have<br />
sex with men. Annals of Behavioral Medicine<br />
25:203-13, 2003.<br />
Lemanek, KL, Brown, RT, Armstrong, FD,<br />
Hood, C, Pegelow, CH, and Woods, G. Dysfunctional<br />
eating patterns and symptoms of pica in<br />
children and adolescents with sickle cell disease.<br />
Clinical Pediatrics 41:493-500, 2002.<br />
Perrin, E and the Committee on Psychosocial<br />
Aspects of Child and Family Health, American<br />
Academy of Pediatrics. (Armstrong, FD, coauthor),<br />
Technical report: co-parent or secondparent<br />
adoption by same-sex parents. Pediatrics<br />
109:341-344, 2002.<br />
Thompson, RJ, Jr, Armstrong, FD, Link, CL,<br />
Pegelow, CH, Moser, F, and Wang, W. A prospective<br />
study of the relationship over time of behavior<br />
problems, intellectual functioning, and family<br />
functioning in children with sickle cell disease: a<br />
report from the Cooperative Study of Sickle Cell<br />
Disease. Journal of Pediatric Psychology 28:59-<br />
65, 2003.<br />
Fernandez, M, Porosnicu, M, Markovic, D, and<br />
Barber, GN. Genetically engineered vesicular stomatitis<br />
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Koniaris, LG, Wilson, S, Drugas, G, and<br />
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Koniaris, LG, McKillop, IH, Schwartz, SI, and<br />
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Hepatology 38:326-34, 2003.<br />
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G L O S S A R Y<br />
G L O S S A R Y<br />
2-DG—2 deoxyglucose<br />
ACDU—Automatic Cell Deposition Unit<br />
ACS—American <strong>Cancer</strong> Society<br />
ALL—acute lymphocytic leukemia<br />
AMC—AIDS Malignancy Consortium<br />
AML—acute myeloid leukemia<br />
APC—antigen presenting cell<br />
ATL—adult T-cell leukemia<br />
AZT—azidothymidine<br />
BEA—blastocyst engraftment assay<br />
BF—benefit-finding<br />
BMT—bone marrow transplantation<br />
CBSM—cognitive-behavioral stress management<br />
CBCTR—Cooperative Breast <strong>Cancer</strong><br />
Tissue Resource<br />
CDC—<strong>Center</strong>s for Disease Control<br />
Cdk—cyclin-dependent kinase<br />
CK—cytokeratin<br />
CLL—chronic lymphocytic leukemia<br />
CMT—chemically-modified tetracycline<br />
CNS—central nervous system<br />
COL-3—chemically modified non-antimicrobial<br />
tetracycline<br />
CPOR—<strong>Center</strong> for Psycho-Oncology Research<br />
CPT—natural product camptothecin<br />
CTL—cytotoxic T lymphocytes<br />
DC—dendritic cells<br />
DLBCL—diffuse large B-cell lymphoma<br />
DR3—death receptor 3<br />
DSMB—Data and Safety Monitoring Plan<br />
EBV—Epstein-Barr virus<br />
ECM—extracellular matrix<br />
EGF—epidermal growth factor<br />
EMSA—electromobility shift assay<br />
ER—estrogen receptor<br />
ERM—ezrin, radixin, and moesin<br />
ER/PR—estrogen receptor/progesterone receptor<br />
ES—embryonic stem<br />
EST—expressed sequence tag<br />
FAMRI—Flight Attendant Medical Research<br />
Institute<br />
FDA—Food and Drug Administration<br />
FCCCI—Florida <strong>Comprehensive</strong> <strong>Cancer</strong><br />
Control Initiative<br />
FCDS—Florida <strong>Cancer</strong> Data System<br />
FDOH—Florida Department of Health<br />
FLRF—fetal liver ring finger<br />
FRAP—fluorescence recovery after photo<br />
bleaching<br />
FRET—fluorescence resonance energy transfer<br />
GC—germinal center<br />
GCRC—General Clinical Research <strong>Center</strong><br />
GI—gastrointestinal<br />
GIS—geographic information system<br />
GM-CSF—granulocyte macrophage-colony<br />
stimulating factor<br />
GPI—glycosil-phosphatidil-inositil<br />
GVHD—graft versus host disease<br />
HA—hyaluronic acid<br />
HAASE—hyaluronidase<br />
HAM/TSP—HTLB-associated myelomathy/<br />
tropical spastic paraparesis<br />
HCC—hepatocellular carcinoma<br />
HCV—hepatitis C virus<br />
HGAL—human germinal center-associated<br />
lymphoma<br />
HHV—human herpes virus<br />
HIF—hypoxic inducible factor<br />
HIV—human immunodeficiency virus<br />
HNSCC—head and neck squamous cell carcinoma<br />
HPV—human papilloma virus<br />
HSC—hematopoietic stem cells<br />
HSV—herpes simplex virus<br />
HTLV-I—human T-lymphotropic virus type I<br />
HYAL1—hyaluronidase<br />
IF—intermediate filament<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong><br />
191
G L O S S A R Y<br />
IFN—interferon<br />
IL—interleukin<br />
INCA—National <strong>Cancer</strong> Institute of Brazil<br />
IND—Investigational New Drug<br />
INOS—inducible nitric oxide synthase<br />
IRB—Institutional Review Board<br />
KO—knock-out<br />
LAK—lymphokine-activated killer cells<br />
LCM—laser capture dissection microscope<br />
LSC—laser scanning cytometer<br />
MAPK—mitogen-activated protein kinase<br />
MDR—multiple drug resistance<br />
MHC—major histocompatability complex<br />
MIC-1—macrophage inflammatory cytokine-1<br />
MIS—MetaMorph Imaging System<br />
MM—multiple myeloma<br />
MMPs—matrix metalloproteinases<br />
mRNA—messenger RNA<br />
mtDNA—human mitochondrial DNA<br />
MTOC—microtubule organizing centers<br />
MUC1—human mucin 1<br />
NASA—National Aeronautics and<br />
Space Administration<br />
NCI—National <strong>Cancer</strong> Institute<br />
NCI-DTP—National <strong>Cancer</strong> Institute-<br />
Developmental Therapeutics Program<br />
NGF—nerve growth factor<br />
NHL—non-Hodgkin lymphoma<br />
NHLBL—National Heart, Lung, and<br />
Blood Institute<br />
NIEHS—National Institute of Environmental<br />
Health Sciences<br />
NIH—National Institutes of Health<br />
NIOSH—National Institute of Occupational<br />
Safety and Health<br />
NK—natural killer<br />
NKB—Dutch <strong>Cancer</strong> Foundation<br />
NKCC—natural killer cell cytotoxicity<br />
NMR—nuclear magnetic resonance<br />
NO—nitric oxide<br />
NPC—nuclear pore complexes<br />
Nups—nucleoporins<br />
ORF—open reading frame<br />
OXPHOS—oxidative phosphorylation<br />
PCMR—Pediatric Cardiomyopathy Registry<br />
PCNA—proliferating cell nuclear antigen<br />
PCR—polymerase chain reaction<br />
PDIP1—polymerase delta interacting protein-1<br />
PDK1—phosphoinositide-dependent protein<br />
kinase-1<br />
PEL—primary effusion lymphomas<br />
PEMs—peritoneal elicited macrophages<br />
PGCs—primordial germ cells<br />
PH—pleckstrin homology<br />
PKB—protein kinase B<br />
PKC—protein kinase C<br />
Polε—polymerase epsilon<br />
QLACS—quality of life in adult cancer survivors<br />
Rb—retinoblastoma<br />
RENCA—renal cell carcinoma<br />
RT—reverse transcriptase<br />
RTOG—Radiation Therapy Oncology Group<br />
SCCA—squamous cell carcinoma<br />
SCID—severe combined immunodeficiency<br />
disease<br />
SIL—squamous intraepithelial lesions<br />
SIR—standardized incidence ratios<br />
SMC—sialomucin complex<br />
TBIO—thermodynamically balanced inside-out<br />
TGF-α—transforming growth factor-alpha<br />
TGF-β—transforming growth factor-beta<br />
TNF—tumor necrosis factor<br />
UM/<strong>Sylvester</strong>—University of Miami <strong>Sylvester</strong><br />
<strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong><br />
VEGF—vascular endothelial growth factor<br />
VSV—vesicular stomatitis virus<br />
wt—wild type<br />
192<br />
UM/<strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong> Scientific Report <strong>2004</strong>
University of Miami <strong>Sylvester</strong> <strong>Comprehensive</strong> <strong>Cancer</strong> <strong>Center</strong><br />
1475 N.W. 12th Avenue<br />
Miami, Florida 33136<br />
UM/<strong>Sylvester</strong> at Deerfield Beach<br />
1192 East Newport <strong>Center</strong> Drive, Suite 100<br />
Deerfield Beach, Florida 33442<br />
www.sylvester.org<br />
305-243-1000 / 1-800-545-2292