Project Summary About 50% of high grade serous ovarian cancers (HGSOC) exhibit defects in homologous recombination (HR; e.g. BRCA1/2 mutations). Approximately 20% HGSOC and 50% of serous endometrial cancer (EMCA) exhibit CCNE1 amplification. About 50% clear cell ovarian cancer (CCOC) have ARID1A loss. My research goal is to exploit genetic vulnerabilities in gynecological cancers with scientifically rational drug combinations. First, CCNE1 amplification promotes loss of G1-S checkpoint and increased reliance on the G2-M checkpoint for survival. Ovarian and endometrial cancers with CCNE1 amplification are platinum resistant with poor outcomes. I will test new therapies that exploit survival pathways critical for survival in CCNE1 oncogene addicted cells. I will also determine if other biomarkers in addition to CCNE1 correlate with response to effective targeted therapies. Second, rare gynecological cancers lack preclinical models for drug discovery. We will expand our existing PDX and organoid platform to include rare tumor types. We will also test new strategies that exploit the genetics of these rate tumor types such as low-grade serous ovarian cancer. In addition, I will perform deep genomic and transcriptomic studies to identify biomarker signatures that predict response to DNA Damage Response (DDR) inhibitor combinations using PDXs and patient samples from an ongoing phase IB clinical trial. I will also identify new targets for ARID1Amut clear cell ovarian cancer using a CRISPR screen targeting functional protein domains. Lastly, PARP inhibitors (PARPi) represent a significant advance in ovarian cancer treatment with HR deficiency; however, tumors ultimately acquire resistance. I showed that combination PARPi-ATRi overcomes PARPi resistance in cell lines and PDX models (Nature Commun, 2020) which led to Phase II clinical trial. We will now determine if combination therapy can be augmented by activating the immune system. We will test new strategies such as radionucleotides to overcoming PARPi resistance. Lastly, we will further evaluate a non-invasive molecular imaging tool to predict response to PARPi therapies. In summary, these studies have a significant impact to advance cancer therapies for women with gynecological malignancies into the clinic.