Elucidating a novel metabolic mechanism of glucosamine-driven treatment resistance in castration-resistant prostate cancer through stimulation of 3b-HSD1-mediated DHEA metabolism - SUMMARY
Prostate cancer (PCa) is the most common cancer among men in the United States, with an estimated
191,930 new cases in 2020 and 33,330 deaths. PCa progression depends primarily on androgen signaling,
and thus androgen deprivation therapy (ADT) is the first-line treatment for advanced PCa. Acquired resistance
to ADT and progression to castration-resistant prostate cancer (CRPC) occurs in nearly all patients, in part due
to continued androgen synthesis from extragonadal precursor steroids. 3β-hydroxysteroid dehydrogenase-1
(3β-HSD1) is the first enzyme responsible for metabolizing the adrenal androgen, DHEA, to more potent
downstream androgens, and has been demonstrated to play a critical role in CRPC. Our preliminary studies
identified glucosamine as having a role in enhancing 3β-HSD1 enzymatic activity in PCa cells. I propose to
investigate a novel metabolic mechanism of glucosamine-driven treatment resistance in castration-resistant
prostate cancer through stimulation of 3β-HSD1-mediated DHEA metabolism. Altered glucosamine
metabolism, including enhanced downstream O-GlcNAcylation, has been demonstrated to occur in the
metabolic dysfunction of Type 2 diabetes (T2D). Associations between T2D and outcomes in PCa have been
long recognized, but the underlying mechanisms are not clearly defined. Further, hormonal treatment itself
results in metabolic syndrome in > 50% of treated men. I hypothesize that the metabolic syndrome that
occurs as a consequence of ADT results in elevated glucosamine that can ultimately drive treatment resistance
through effects on 3β-HSD1 and androgen metabolism. Aim 1 will delineate the mechanism by which
glucosamine enhances 3β-HSD1 transcription and enzymatic activity. Aim 2 will interrogate the role of
glucosamine in 3β-HSD1-mediated DHEA metabolism and CRPC development in vivo. Aim 3 will assess the
clinical relevance of glucosamine-mediated increased androgen metabolism in PCa progression, including its
role in mediating responses to hormonal therapy. The findings of this project have the potential to inform
comprehensive therapeutic strategies in the treatment of CRPC that take into consideration ameliorating or
targeting the metabolic disturbances of ADT. This work will be conducted at the Lerner Research Institute at
Cleveland Clinic in the lab of Dr. Nima Sharifi. Through completion of this project, I will expand my knowledge
and skills in prostate cancer biology and translational research. Coursework and workshops on these topics
will supplement my research-based training. As part of my career development plan, I will also work to improve
my science communication skills and gain leadership experience through regular presentations, taking part in
our institute's science communication program, teaching an undergraduate biology course, and serving on our
postdoctoral association committee. I am confident that through completion of this fellowship, I will make a
significant contribution to the field of prostate cancer research, will successfully transition into a role as an
independent scientist, and will go on significantly influence the field and patient care.
