PROJECT SUMMARY This is a proposal for a five-year career development program to study hormonally-determined metabolic programs as therapeutic targets for prostate cancer. The candidate is currently an Instructor of Oncology at Johns Hopkins University School of Medicine. The proposal builds on the candidate’s previous research and clinical experience and integrates two distinct areas of expertise of her mentors, Dr. Samuel Denmeade and Dr. Erika Pearce, to understand metabolic vulnerabilities induced by high dose androgen in prostate cancer. In spite of recent advances in prostate cancer therapy development, this disease continues to kill more than 350,000 men per year worldwide. Standard-of-care therapies inhibit androgen receptor (AR) signaling, which often leads to adaptive upregulation of AR to drive resistance. We have shown that this upregulation of AR constitutes a vulnerability to high dose androgen and are developing a novel therapy called Bipolar Androgen Therapy (BAT) in which high dose androgen is provided intermittently to result in cycling of serum androgens to minimize adaptations to high or low levels of androgens. To date, our clinical trials indicate that BAT is safe, improves quality of life, and can induce responses in a subset of patients for whom there are very limited therapeutic options. We are now seeking to expand the population of patients who benefit from BAT by identifying metabolic synthetic lethal vulnerabilities induced by exposure to high levels of androgens in the initial phase of BAT. This proposal focuses on identifying metabolic vulnerabilities because (1) a fundamental effect of androgens across numerous tissues in the body, including benign and malignant prostate, is alteration of cellular metabolism and (2) metabolic plasticity is an emerging common pathway of resistance to cancer therapies. Our preliminary data using global metabolomics and a metabolism-focused CRISPR-based genetic screen indicate that high dose androgen dramatically reprograms prostate cancer metabolism resulting in vulnerabilities including de novo polyamine synthesis and nucleotide synthesis. Specific aims proposed will interrogate synthetic lethality of high dose androgen in combination with inhibition of polyamine synthesis (Aim 1) and with inhibition of nucleotide synthesis (Aim 2). Aim 3 will assess efficacy of combination therapies across a highly characterized panel of patient-derived xenograft models of castration-resistant prostate cancer that approximate the diversity of patients with this disease. The outlined career development and research plan will provide the candidate with unique cross-disciplinary skills that will enable her transition to independence as a physician scientist and identify promising combination therapies for treatment of patients with castration-resistant prostate cancer.