SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
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 the 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 the 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 the animals
with the drug significantly reduced the incidence
of tumor at the site of tumor cell injection. Their
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demonstration of 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 Division of the National
Cancer Institute (NCI-DTP). In a recently
concluded first human clinical phase I trial of
COL-3, the NCI-DTP recommended COL-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 wide interest in the use of COL-3
among many investigators within and outside the
University of Miami; a new patent was 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 on
identifying novel combination therapies for advanced
hormone-refractive prostate cancer.
Dr. Lokeshwar’s research for this study also
was funded by two consecutive grants from the
Department of Defense Congressionally Directed
Medical Program on Prostate Cancer. In its summary
report to the U.S. Congress, his research was
highlighted as one of the most significant outcomes
of the CDMRP Prostate Cancer Program.
SELECTED PUBLICATIONS
2002
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern, M, and Pflugfelder, SC.
Experimentally induced dry eye produces ocular
surface inflammation and epithelial disease. Advances
in Experimental Medicine and Biology
506(Pt A):647-55, 2002.
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern, ME, and Pflugfelder, SC.
A mouse model of keratoconjunctivitis sicca. Investigative
Ophthalmology & Visual Science
43:632-38, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004