The goal of this proposal is to understand the connection between epigenetic regulation and ovarian cancer and to begin to leverage these findings into the development of novel therapeutic strategies. The specific goals of this proposal are to (1) Determine the epigenetic drivers and drug targets in ovarian cancer, (2) Determine the mechanism of action of these targets and their pathophysiology, (3) Leverage our understanding of chromatin regulatory mechanisms to the development of targeted small molecule inhibitors for epithelial ovarian cancer (EOC) including ovarian clear cell carcinoma (OCCC) treatment, and (4) Develop strong preliminary data and further integration of projects for a NCI program project application in “Chromatin regulatory mechanisms in ovarian cancer and implications for novel therapies” for the next year. To achieve the goals of the proposal, we have assembled a group of investigators from University of Pennsylvania/Wistar Institute campus with combined scientific expertise in cancer, tumor microenvironment and chromatin regulation and complimentary technical expertise in cell biology, mouse genetics, biochemistry, structural biology, biomarkers, proteomics and protein inhibitor development. These investigators have a strong record of NCI funding in basic and translational ovarian cancer and/or chromatin regulation, and have now co-published more than 20 research articles together. The program will be a continuation of the previous funding cycle and include four hypothesis-driven projects. Project 1, co-led by Drs. Rugang Zhang and Dave Speicher, will study the mechanistic basis and therapeutic targeting of ARID1A mutation in ovarian cancers. Project 2, led by Dr. José Conejo-Garcia, will elucidate how Satb1 governs Treg activity in ovarian cancer. Project 3, led by Dr. Frank Rauscher, will study the role of the master regulator transcription factors Twist, Snail and Slug in malignant progression of ovarian cancer. Project 4, led by Dr. Ronen Marmorstein, will study the roles of the acetylated TCEAL7 tumor suppressor and HBO1 protein acetyltransferase in ovarian cancer. Importantly, the success of these projects will continue to depend on the combined scientific and technical expertise of the group.Together, these studies set the stage for the most comprehensive understanding of how chromatin biology impacts therapeutic targeting approaches by taking advantage of the newly gained mechanistic insights in EOC.