Abstract 4654: Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs

Abstract High-grade serous ovarian cancer (HGSOC) is remarkably responsive to chemotherapy and yet recurs at high rates as resistant disease. Using novel technology that selects for rare clonogenic cells which recapitulate HGSOC in immunodeficient mice, we have identified, in therapy-naive HGSOC, a minor population of clones that are intrinsically resistant to paclitaxel/carboplatin as well as to a broad spectrum of oncology drugs. These intrinsic "polyresistant" cells are a common, albeit minor, component of clonogenic cells in all therapy-naive tumors analyzed. Importantly, the polyresistant clonogenic cells share a gene expression signature distinct from the majority of clonogenic cells that are exquisitely sensitive to paclitaxel/carboplatin, and this gene signature of polyresistant cells extends to all polyresistant clones within a patient and across HGSOC cases. We have exploited these polyresistant clones to perform high-throughput screening of small molecule "bioactive" libraries to identify compounds that circumvent this resistance. While single agent "hits" were obtained, these showed minimal therapeutic windows relative to normal stem cells of the liver and gastrointestinal tract. Adaptations of synthetic lethal strategies have yielded lead drug combinations that eliminate polyresistant clones from all four cases tested at low nanomolar concentrations in vitro. We have improved these combinations via the synthesis of new chemical entities that show potent effects against both subcutaneous and peritoneal tumor models in immunodeficient mice derived from polyresistant HGSOC clones. Clonogenic analyses of these treated and untreated xenografts support the notion that these drug combinations are targeting the stem cell populations within these tumors. We anticipate that these drug combinations will assist in preventing or treating recurrent HGSOC. Citation Format: Wa Xian, Frank McKeon, Christopher Crum, Jaffer Ajani, Peter Davies, Matthew Vincent, William Bachovchin, Hung-Sen Lai, Shuang Pan, Melina Khorrami, Melika khorrami, Raul caballero Montes, Paria Mosaffa, Ashley Hoffman, Amber Su. Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4654.