Scientific Objective: Prostate cancer is the most common cancer among American men, with 238,590 estimated new cases diagnosed in the United States in 2013. Approximately 30% of patients require hormone therapy in the form of androgen deprivation, also called "chemical castration." However, most of these patients will eventually develop resistance to hormone therapy. This relapsed disease is called castration resistant prostate cancer (CRPC) and is responsible for almost all prostate cancer deaths in the United States (~30,000 annually). Because the lack of effective conventional therapies, this disease is one of the most difficult cancers to treat. Thanks to the research efforts of Dr. Charles Sawyers' laboratory, a novel drug called enzalutamide (Xtandi) targeting the androgen receptor pathway (a critical pathway for cancer cell survival) was developed. Unfortunately, despite the exciting clinical success of enzalutamide, about 50% of patients showed various degree of resistance to this agent. This high variability in response limits the clinical benefit of this novel drug, underscoring the importance of understanding the mechanisms of enzalutamide resistance.

My project aims to address the connection between the genomic heterogeneity of advanced prostate cancer and distinct initial sensitivities to enzalutamide prior to the development of resistance. I will further identify the biomarkers responsible for differences in initial response to this novel treatment via a cutting-edge approach called shRNA-based library screening. The clinical relevance of these candidate biomarkers will be validated using clinical samples obtained from enzalutamide treated patients at Memorial Sloan Kettering Cancer Center (MSKCC). I expect that the completion of this project will not only add clarity to genetic subtypes of advanced prostate cancer, but also lead to the development of new drug targets and target therapies, consequently providing greater clinical benefit to patients with CRPC.

Career Goals: My goal is to become an independent investigator focused on understanding the biological basis of prostate cancer. I am now completing my postdoctoral training under the mentorship of Dr. Charles Sawyers at MSKCC. MSKCC is a premier cancer treatment and research center, and Dr. Sawyers is a leading prostate cancer investigator, whose recent work led to the development of a new generation of drug (enzalutamide) targeting a pathway critical for prostate cancer survival. The project that I proposed aims to identify biomarkers responsible for the variable response to this novel drug, leading to the development of new agents that would overcome drug resistance and benefit patients with advanced prostate cancer. With all the resources provided by the Sawyers' laboratory and the support from the Prostate Cancer Research Program, I believe that completion of this proposed project will provide excellent preparation for my career as an independent scientist in the prostate cancer research field.

Applicability of the Research: Approximately, 30% of patients with prostate cancer will require hormone therapy and most of these patients will eventually develop resistance to conventional therapy. The research led by my mentor, Dr. Sawyers, led to the development of the novel drug enzalutamide for CRPC. The variable responses to enzalutamide largely limit the clinical benefit of this novel agent. My proposed project aims to identify potential biomarkers that confer resistance to enzalutamide and consequently lead to the development of new drug treatments or combined therapies. Supported by the unparalleled resources of MSKCC, the clinical relevance of the candidate biomarkers identified by my proposed research will be quickly validated using clinical samples obtained from enzalutamide-treated patients at MSKCC. The completion of my proposed project will add clarity to genetic subtypes of advanced prostate cancer and may also lead to the development of new drug targets and target therapies, consequently providing greater clinical benefit to patients with castration resistant prostate cancer.

Expected Contributions of the Study to Prostate Cancer Research: The various responses to enzalutamide treatment largely limit the clinical benefit of this novel agent, thus understanding the mechanisms of primary enzalutamide resistance is of significant interest to the prostate cancer research community. The experiments in my proposal are designed to investigate the connection between primary enzalutamide resistance and the genetic heterogeneity of prostate cancer to further identify biomarkers responsible for variation of response to enzalutamide. The completion of this project will shed light on the mechanism of primary enzalutamide resistance, add clarity to genetic subtypes of advanced prostate cancer, and lead to the development of novel agents or combination therapy that would overcome enzalutamide resistance. This work will not only advance the prostate cancer research field, but also provide greater clinical benefit to patients with advanced prostate cancer.