Abstract B055: Identifying compounds to promote apoptotic cell death in clear cell ovarian cancer

Abstract Clear cell ovarian cancer is a rare subtype of ovarian cancer with a poor prognosis in advanced-stage disease and increased resistance to standard-of-care treatments including platinum chemotherapy. Previously, we found that multiple clear cell ovarian cancer cell lines are sensitive to inhibition of BCL-XL, a pro-survival member of the BCL-2 family of proteins that control mitochondrial apoptosis. Adding a BCL-XL inhibitor also enhances cell death in clear cell ovarian cancer cell lines treated with standard-of-care drugs including cisplatin, paclitaxel, and poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. To more broadly identify compounds that affect the viability of clear cell ovarian cancer cell lines, either alone or in combination with BCL-XL inhibition, we applied a chemical screening approach. We designed an anchor screen strategy in which a chemical library of clinically relevant compounds (Selleck bioactive compound library; 1, 902 compounds) was screened against clear cell ovarian cancer cell lines in two sets: library compounds only, or library compounds combined with BCL-XL inhibitor A1331852 at a fixed concentration (IC25 for each cell line). Fold-change in cell number compared to controls and Z-scores were calculated to identify compounds with single-agent activity in clear cell ovarian cancer and/or with enhanced activity in the presence of A1331852. Initial screening data from JHOC5 and OVISE cell lines identified compounds with targets such as SYK and other tyrosine kinases, PI3K/AKT, and BCL2, as well as chemotherapies, which demonstrated increased activity in the presence of BCL-XL inhibition. Screening of additional cell lines and validation of candidate hits is ongoing to identify agents that are active alone or in combination with BCL-XL inhibition against clear cell ovarian cancer. Citation Format: Brendan Shay, Abram Handly-Santana, Xingping Qin, Jonathan Choniere, Kristopher Sarosiek, Joan S. Brugge, Elizabeth H. Stover. Identifying compounds to promote apoptotic cell death in clear cell ovarian cancer abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B055.