Novel Regulators of Lineage Plasticity in Castration-Resistant Prostate Cancer

Objective: The proposed research project will seek to identify key factors that drive therapy resistance and metastasis in castration-resistant prostate cancer (CRPC). Rationale: Prostate cancer is the most commonly diagnosed cancer in North American men and the second leading cause of cancer-related death. Androgen deprivation therapy (ADT) is the treatment of choice for primary prostate cancer and is initially effective. However, the development of CRPC is nearly inevitable. Key findings have shown that CRPC still has active androgen receptor (AR), since it has ways to activate its AR that are independent of androgens such as testosterone. Thus, drugs that target AR activity, such as enzalutamide, can still inhibit the growth of CRPC. Although these drugs have improved the survival of patients with CRPC, resistance and metastasis still occur, with many patients eventually progressing to lethal prostate cancer. Further studies have demonstrated that CRPC is often a highly heterogeneous tumor containing a mixture of AR-active prostate cancer (ARPC) and AR-negative prostate cancer, such as neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that does not express AR or have neuroendocrine features. In particular, AR-negative forms of CRPC may facilitate drug resistance and promote progression to lethal prostate cancer. NEPC is the most aggressive and lethal form of prostate cancer that lacks effective treatments. Work from our laboratory and others have shown that NEPC arises from ARPC, but whether it is directly from ARPC or through AR-negative prostate cancer is unknown. Therefore, there is an urgent need to understand the emergence of NEPC and to identify key factors that drive its therapy resistance. Ultimate Applicability: In preliminary studies for this proposal, I have used genetically engineered mice to create a model that can successfully capture these variant forms of CRPC and resembles human aggressive prostate cancer. In my studies, I will use this mouse model together with computational analyses to identify key factors that drive the emergence of therapy-resistant forms of CRPC. I will use innovative computational approaches to predict drugs that target these key factors. Moreover, I will pursue systematic drug response assays in our established mouse models to identify specific and effective compounds that can inhibit or possibly convert therapy-resistant forms of CRPC to therapy-sensitive ones. Thus, my proposed studies may ultimately lead to the development of new drugs for use in potential combination therapies to treat human lethal prostate cancer. Therefore, my studies may improve the quality of life of those prostate cancer patients who relapse with more aggressive forms of the disease. Taken together, my proposed research should lead to a greater understanding of the processes that control the formation of NEPC and, in the short term, will directly address the FY21 PCRP Overarching Challenges of defining the biology of lethal prostate cancer to reduce death. Over a longer term, my work should also have strong impact on development of treatments that improve outcomes for men with lethal prostate cancer. Principal Investigator's Career Goals: My primary career goal is to establish an independent laboratory at a university or biomedical research center to pursue the in-depth understanding of the process of prostate cancer progression and metastasis and to contribute the movement of new ideas and effective treatments from the laboratory to the clinic. My proposed research project will require learning comprehensive techniques and developing expertise in prostate cancer research and translational studies. In addition, I will acquire experience in communication, presentation, and collaboration in order to design my research and efficiently accomplish this project. Therefore, the proposed research project will promote my development into an independen