Dissecting FOSL1-mediated lineage plasticity and resistance to androgen receptor signaling inhibition in prostate cancer

PROJECT SUMMARY/ABSTRACT CANDIDATE: I am a postdoctoral research associate in the laboratory of Dr. Yu Chen in the Human Oncology and Pathogenesis Program (HOPP) at Memorial Sloan Kettering Cancer Center. My PhD training at Boston University School of Medicine under the supervision of Dr. Sam Thiagalingam allowed me to develop cellular

and molecular biological skills to functionally characterize candidate genes involved in cancer progression and investigate therapeutic vulnerabilities. My current research focuses on utilizing patient-derived organoid models to define epigenetic subtypes of castration resistant prostate cancer (CRPC) and determining the dependency

on transcription factors to mediate growth and lineage identity. My proposed research and mentoring plan will provide me with a strong foundation towards becoming an independent investigator in academia. My long-term career goal is to advance personalized cancer medicine, with specific interests in disease modeling, functional

characterization of drivers of lineage plasticity, and evaluation of therapeutics to target oncogenic dependency. To achieve this goal, I have developed a career plan that will ensure my success to becoming an independent investigator by: 1) bolstering my scientific knowledge and technical expertise, 2) assembling an advisory

committee to oversee my training progress, 3) improving my communication skills, 4) expanding my professional network, and 4) preparing me for leading and mentoring future trainees. RESEARCH: Prostate cancer depends on androgen receptor (AR) signaling for growth and survival. The advent of therapies targeting AR signaling has driven the disease towards AR-independence. Using a

functional genomics approach, we have identified a new epigenetic subtype of CRPC called stem cell-like (SCL), which is driven by FOSL1 and lacks therapeutic options. Genetic perturbation of FOSL1 and its cooperating factors YAP/TAZ leads to impaired cell growth and loss of SCL lineage, suggesting that CRPC-

SCL cells are dependent on FOSL1 for survival. Building on these discoveries, in this proposal, I aim to: 1) Define the role of FOSL1 in mediating lineage plasticity and resistance to enzalutamide in prostate cancer and 2) Evaluate therapeutics to target the YAP/TAZ/TEAD/FOSL1 pathway in the stem cell-like subtype of prostate

cancer. ENVIRONMENT: The Yu Chen laboratory is a part of the HOPP under the leadership of Dr. Charles Sawyers at Memorial Sloan Kettering Cancer Center, a top-tier institute in cancer research. The primary mentor is Dr. Yu Chen, a pioneer in developing prostate cancer organoids from patients and an expert in the study of

epigenetics and aberrantly activated transcriptional programs. Furthermore, my advisory committee and collaborator will provide additional support for the proposed research and career development plans.