Targeting Chromatin Modifiers to Treat Ovarian Cancer

Project summary

2023 Early Career Investigator Grant

University of Pennsylvania

Epithelial ovarian cancer is the most frequent cause of gynecologic malignancy-related mortality in women in the United States. Over the past 30 years standard treatments for newly diagnosed ovarian cancer have consisted of cytoreductive surgery followed by platinum-taxane chemotherapy. After initial chemotherapy, the majority of women with ovarian cancer will have a relapse of their disease and require additional treatment. Recently, limited targeted-therapy options, such as PARPis, have been approved to treat ovarian cancer. However, the greatest clinical benefit from PARPi therapy has mainly been observed in patients with homologous recombination (HR) deficiency. Moreover, tumors initially HR-deficient commonly acquire HR-proficiency after PARPi treatment by restoration of HR function, thereby becoming resistant to PARPis. Therefore, there is an urgent unmet medical need to develop alternative therapeutic strategies for patients with ovarian cancer. A growing emphasis in ovarian cancer drug discovery efforts has been on targeting chromatin modifiers (i.e., chromatin-remodeling enzymes and histone-modifying enzymes). Challenges in target identification and characterization have resulted in a narrow focus on the development of epi-drugs for ovarian cancer therapy. We hypothesize that combination of chemical/genetic screen and multidimensional profiles of genome, functionome, and druggome can identify novel epi-drug targets and combinations for ovarian cancer treatment.

This grant was made possible in part by a generous donation by the Melitta S. and Joan M. Pick Charitable Trust.