Dr. Hari Koul Presents Work on Prostate Cancer at March Dean’s Seminar
Dr. Hari K. Koul presented for the School of Medicine Dean’s seminar in March. The
title of the presentation was “Prostate Cancer Progression and Therapeutic Resistance:
Role of Prostate Derived Ets Factor (PDEF).” The presentation started off with the
statement that, “In the United states, PCa is the most diagnosed cancer in men and
is the second leading cause of cancer deaths in men.” Dr. Koul presented recent data
from Cancer Facts and Statistics from the American Cancer Society showing an estimated
248,530 new cases and 34,130 deaths from prostate cancer (PCa) in the USA in 2021.
Interestingly, in a majority of men, prostate cancer may present as an indolent disease.
However, due to lack of specific markers that can accurately differentiate between
men with indolent disease and lethal disease, all the men with diagnosis of PCa have
to be treated.
New targets that distinguish men with lethal prostate cancer from those with indolent
disease are currently an unmet need. Current treatment modalities for PCa patients
include surgery, radiation therapy, cryotherapy, and in some cases active surveillance
for organ-confined disease. If the disease spreads outside the prostate gland (metastatic
disease), hormone therapy is the first line of treatment. Additional data were presented
by Dr. Koul indicating that there are many excellent options for the patients with
organ-confined disease, but we still do not have any curative treatments for the patients
with metastatic PCa who fail hormone ablation therapies – another factor highlighting
the need for research that tackles therapy resistant PCa. Dr. Koul also reviewed the
origins of hormone therapy for PCa and presented insights on the molecular mechanisms
of action for androgen in PCa.
To show how his laboratory is working to address the many issues surrounding PCa,
Dr. Koul presented data from his ongoing studies examining the molecular mechanisms
of PCa progression and therapeutic resistance. In particular, he highlighted his
laboratory’s studies on the role of PDEF/SPDEF, an ETS transcription factor. The
Koul laboratory was the first to observe loss of an ETS transcription factor during
PCa progression. They further found that the decreased expression/loss of PDEF during
PCa progression was reciprocally coupled with over expression/gain of Twist-1, one
of the master regulators of epithelial to mesenchyme transition (EMT). Additional
mechanistic studies indicated that decreased expression/loss of PDEF directly regulated
CK18, a prostate luminal epithelial-specific cytokeratin by PDEF. These mechanistic
studies also revealed that PDEF selectively modulated the expression of genes associated
with cell migration and cell invasion. More specifically, PDEF inhibited EMT and
modulated PCa progression, in part, by limiting cellular plasticity and maintaining
a luminal cell phenotype (see figure, left). Luminal cells are also important in that
they are the only cells in the prostate that are responsive to androgen and androgen
receptor modulating therapies. Based on these observations, Dr. Koul hypothesized
that these studies of PDEF expression could revitalize studies previously funded by
a NCI-RO1 and VA Merit Award, which were focused on understanding the role of PDEF
in PCa health disparities and in modulating AR cistrome and lineage plasticity in
PCa, respectively. In summarizing, Dr. Koul reiterated the importance of these types
of mechanistic studies for the purpose of slowing down tumor progression and reversing
therapeutic resistance, and ultimately extending the survival of patients diagnosed
with PCa.
Koul laboratory was the first to observe loss of an ETS transcription factor during
PCa progression. They further found that the decreased expression/loss of PDEF during
PCa progression was reciprocally coupled with over expression/gain of Twist-1, one
of the master regulators of epithelial to mesenchyme transition (EMT). Additional
mechanistic studies indicated that decreased expression/loss of PDEF directly regulated
CK18, a prostate luminal epithelial-specific cytokeratin by PDEF. These mechanistic
studies also revealed that PDEF selectively modulated the expression of genes associated
with cell migration and cell invasion. More specifically, PDEF inhibited EMT and
modulated PCa progression, in part, by limiting cellular plasticity and maintaining
a luminal cell phenotype (see figure, left). Luminal cells are also important in that
they are the only cells in the prostate that are responsive to androgen and androgen
receptor modulating therapies. Based on these observations, Dr. Koul hypothesized
that these studies of PDEF expression could revitalize studies previously funded by
a NCI-RO1 and VA Merit Award, which were focused on understanding the role of PDEF
in PCa health disparities and in modulating AR cistrome and lineage plasticity in
PCa, respectively. In summarizing, Dr. Koul reiterated the importance of these types
of mechanistic studies for the purpose of slowing down tumor progression and reversing
therapeutic resistance, and ultimately extending the survival of patients diagnosed
with PCa.