SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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
Dadlani, GH, Harmon, WG, Simbre II, VC,
Tisma-Dupanovic, S, and Lipshultz, SE .
Cardiomyocyte injury to transplant: pediatric
management. Current Opinion in Cardiology
18:91-7 (Review), 2003.
Adams, MJ, Hardenbergh, PH, Constine, LS,
and Lipshultz, SE . Radiation-associated cardiovascular
disease. Critical Reviews in Oncology/
Hematology 45:55-75 (Review), 2003.
BALAKRISHNA L. LOKESHWAR, PH.D.
Associate Professor of Urology
DESCRIPTION OF RESEARCH
Dr. Lokeshwar’s research focuses on the
mechanism of prostate cancer metastasis and
its control by novel chemotherapeutic drugs. For
the last several years, Dr. Lokeshwar’s laboratory
has focused on extracellular matrix degradation
and tumor metastasis. His laboratory has studied
the regulation of a class of basement membrane
matrix degrading enzymes called the matrix
metalloproteinases (MMPs) in prostate cancer.
Using cancer cell cultures established from
human prostate tumor tissues obtained after
prostatectomy, they showed that an imbalance
exists between the levels of MMPs (overproduction)
and their natural inhibitors (underproduction)
in invasive prostate cancer cells. Based on
this finding, they developed a hypothesis that a
novel approach to control metastatic cancer is
to correct the imbalance either by inhibition of
secretion of MMPs or by increasing the extracellular
levels of their endogenous inhibitor.
Since several small synthetic inhibitors of
MMPs exist, they tested the usefulness of the inhibitors
using the criteria of oral bioavailability,
systemic toxicity, and ability to target bone metastasis.
In their search for a suitable inhibitor,
Dr. Lokeshwar’s laboratory tested a series of synthetic
tetracycline analogues, which were shown
to possess a strong anti-collagenase activity with
little or no antibiotic activity. Researchers tested
eight different chemically modified tetracyclines
(CMTs) and found one of them, 6-deoxy, 6-
demethyl, 4-dedimethylamino tetracycline
(CMT-3, COL-3, now termed Metastat R by
CollaGenix Pharmaceuticals, Newtown, Pennsylvania),
to be the most promising. Oral dosing
with this analogue to rats and mice-bearing metastatic
prostate tumors reduced tumor growth and
metastasis, with no measurable systemic toxicity.
Furthermore, prophylactic dosing of animals with
the drug significantly reduced the incidence of
tumor at the site of tumor cell injection. Their
demonstration of a highly antimetastatic and antitumor
activity of CMT-3 in a rat prostate tumor
model led to its phase I clinical trial by the
Developmental Therapeutics Program of the NCI
(NCI-DTP). In the recently concluded human
clinical phase I trial of CMT-3, the NCI-DTP
recommended CMT-3 for phase II and phase III
in patients with soft tissue sarcoma and advanced
metastatic tumors. The University of Miami and
the State University of New York at Stony Brook
have jointly obtained a use patent on this drug.
This finding also has generated a wide interest in
the use of CMT-3 among many investigators
within and outside the University of Miami, including
a new patent issued to the University for
the treatment of corneal ulceration in patients
with meibomian gland disease, also called ocular
rosacea. Dr. Lokeshwar’s current research focuses
on identifying novel plant products that have
been used as folk medicine and identifying novel
combination therapies for advanced hormonerefractive
prostate cancer.
In a related development, COL-3 is undergoing
a phase III clinical trial against HIVinduced
Karposi’s sarcoma. Twenty centers
nationwide are engaged in this trial, headed by
Dr. Bruce DeZube of New England Deaconess
Hospital, Boston.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 45