PROJECT SUMMARY ABSTRACT High-grade serous ovarian carcinoma (HGSOC) is the most prevalent histosubtype of epithelial ovarian cancer. Therapy for HGSOC relies on DNA damaging agents, with a high percentage of cancers having de novo or acquired chemoresistance due in part to homologous recombination (HR) proficiency. Our preliminary data has uncovered a potential metabolic mechanism contributing to HR proficiency that could be used for novel targeted therapies for HGSOC. This proposal tests the overarching hypothesis that acetylcarnitine increases site specific histone acetylation post-translational modifications that promote HR-mediated DNA damage repair and allow resistance to standard-of-care DNA damaging agents in HGSOC. Manipulation of acetylcarnitine will therefore sensitize HGSOCs to DNA damaging agents. This project will: 1) quantitatively and mechanistically map the acetylcarnitine-dependent histone acetylation axis and its contribution to HR-mediated DNA repair; and 2) interrogate whether interventions that suppress intracellular acetylcarnitine sensitize HGSOCs to standard-of- care DNA damaging agents. Targeting acetylcarnitine metabolism for sensitization to DNA damaging agents is a novel strategy. Ultimately, this research will help develop metabolic therapeutic strategies against chemoresistance that occurs in many cancer patients.

PROJECT NARRATIVE Epithelial ovarian cancer is the most lethal gynecological malignancy where resistance against current therapies occurs in a high percentage of disease. This project will test a major required metabolic component of this chemoresistance and elucidate targetable steps in chemoresistance.