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 prostat...