LAUSR

Ovarian cancer is the fifth leading cause of cancer death for women in the United States, with only modest improvements in patient survival in the past few decades. Standard-of-care treatment is surgical debulking followed by a combination of platinum and taxane agents, but relapse and resistance frequently occur. In order to identify genes that cause sensitivity or resistance in tumor cells treated with platinum chemotherapeutics, I performed a CRISPRi-based screen that combined decreased gene expression of over 19,000 genes with the platinum drugs cisplatin and oxaliplatin. Genes whose knockdown caused sensitivity to the chemotherapeutics were identified through a multiobjective optimization approach to account for knockdown efficiencies and variances in sequencing depth. To filter the noise in the genome-wide screen and more confidently identify “hits,” a smaller pooled screen of one hundred targets was designed. Genes identified in this focused pooled screen as being important to platinum response in cells will be validated using approaches such as cell viability assays. The molecular mechanisms underlying the function of one or two of these genes in the chemotherapy response will be investigated in further detail. Thus, the project has the potential to define new molecular mechanisms by which tumors resist killing by chemotherapy and provide new therapeutic targets for front-line clinical standard-of-care combination chemotherapy regimes in the treatment of ovarian cancer. Citation Format: Erika D. Handly, Yi Wen Kong, Christian J. Braun, Jesse C. Patterson, Michael B. Yaffe. A CRISPRi screen to identify combination therapies for improved treatment of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A44.