Abstract 1677: Navitoclax, a Bcl-2/xL inhibitor, and YM155, a survivin inhibitor, in combination with carboplatin effectively inhibit ovarian cancer tumor growth

Abstract Introduction: High-grade serous ovarian cancer (OvCa) is generally treated with upfront chemotherapy, including carboplatin. Recurrent disease is driven by the persistence of platinum-resistance cells. Experimental Procedures: A high throughput screen (HTS), using a 3D organotypic culture assembled with extracellular matrix, primary human fibroblasts, and mesothelial cells, was established and validated. Using a library of FDA approved drugs, the 3D HTS was performed with the goal of identifying a combination of drugs that synergistically target two populations of OvCa, aldehyde dehydrogenase (ALDH) high and ALDH low enzyme activity cells, that are less sensitive to carboplatin treatment than the bulk OvCa cells. Summary of Results. Initial results showed that Omipalisib, Verteporfin, CA3, Mitoxantrone, Navitoclax, Venetoclax and YM155 had significant single drug activity in either the ALDH low or both the ALDH low/high cell populations. Synergistic drug activity was identified with three drug combinations, Navitoclax/Omipalisib, Navitoclax/YM155, and YM155/Omipalisib. In vitro the combination of Navitoclax/YM155 was most efficient at blocking primary human OvCa sphere formation and the proliferation of four different OvCa cell lines in the 3D organotypic culture. In vivo the combination of Navitoclax/YM155/carboplatin decreased the total number and weight of metastases, decreased the percentage of ALDH high OvCa cells in tumors, and increased survival when compared to carboplatin treatment alone in xenograft models. Conclusion: Our results suggest that the combination of Navitoclax/YM155/carboplatin has promise as a therapy for the treatment of OvCa. Citation Format: Tejas Samantaray, Hilary Kenny, Lucy Kelliher, Ernst R. Lengyel, Carman K.M. Ip, Kasjusz Kordylewicz, Rachael Hoffmann, Sarah Rauch, Beatrice Malacrida, Sophie Skingsley, Frances R. Balkwill, Chiara Battistini, Ugo Cavallaro, Wolf R. Wiedemeyer. Navitoclax, a Bcl-2/xL inhibitor, and YM155, a survivin inhibitor, in combination with carboplatin effectively inhibit ovarian cancer tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1677.