PROJECT SUMMARY/ ABSTRACT CANDIDATE: My ultimate goal is to become a principal investigator focused on the epigenetic mechanisms driving the pathogenesis of human diseases. I seek to attain a tenure-track position allowing me to establish a research program that studies the epigenetic mechanisms driving breast cancer and the translation of basic research findings into potential new therapies. To achieve my goal, I have developed a career development plan with four key elements: 1) To expand and strengthen my experimental skills and scientific knowledge, 2) To enhance my leadership, mentoring skills, and professional development, 3) To receive support on my career transition from Dr. Ross Levine and research guidance and career support from my collaborators Drs. Maurizio Scaltriti, Sarat Chanderlapaty, Minkui Luo, and Charles Sawyers, Ari Melnick and my advisers Drs. Larry Norton and Ronglai Shen 4) To transition into a tenure-track research independent position. ENVIRONMENT: The proposed study will be conducted at MSKCC, acknowledged for its exceptional patient care, state-of-the-art facilities, and innovative research. I am part of the Human Oncology and Pathogenesis Program (HOPP) that brings together scientists with an interest in mechanism-based laboratory and translational research. Under the leadership of Dr. Charles Sawyers, HOPP creates a highly collaborative environment that will greatly facilitate my translational research efforts. RESEARCH: Alterations in the PI3K pathway occur in 40-60% of ER+ breast cancer or AR+ breast cancer, representing the most common genomic alteration in such tumors, and indicating that the PI3K signaling pathway plays an important role in the tumorigenesis of hormone-dependent tumors. There is important bidirectional regulatory crosstalk between PI3K and ER or AR signaling in breast and prostate cancers respectively, leading to tumors that adapt and survive when either single pathway is pharmacologically inhibited. I have recently demonstrated that PI3K inhibition activates ER function to drive tumor growth in ER+/PIK3CA mutants, through the epigenetic regulator KMT2D. We hypothesized that KMT2D could be a general mechanism in controlling nuclear hormone receptor function and regulate the AR-PI3K crosstalk at cell-specific enhancers of prostate cells. Preliminary data show that KMT2D is required for androgen response upon PI3K inhibition. We now aim to study the molecular mechanisms of KMT2D in the regulation of AR-PI3K crosstalk using prostate cancer cell lines and human prostate organoids (AIM 1 and 2). Furthermore, while searching for epigenetic regulators and their involvement in therapeutic response in ER+ breast cancer, we have also conducted a CRISPR knockout screen that identified the epigenetic regulator ARID1A as the top candidate whose loss mediates resistance to anti-ER therapy through lineage switching. To this end, we aim to dissect the in vivo function and the chromatin- based regulation of ARI...