Abstract 4249: Establishment and analysis of patient-derived high-grade serous ovarian cancer organoids for disease modeling and drug testing

Abstract Purpose: Ovarian cancer is the most lethal gynecologic cancer. Majority of ovarian cancers belong to the subgroup of high-grade serous ovarian cancer (HGSC). Its standard treatment is surgery and chemotherapy with platinum and taxane-based compounds, for which almost all patients become resistant. We have established a panel of patient derived 3-dimensional (3D) HGSC long-term tumor organoid cultures for personalized disease modeling, drug screening and evaluation of the efficiency of potential new treatments to be used in preclinical research. Methods: Tumor tissues or ascites from > 30 HGSC tumors were set up as long-term 3D organoid cultures (PDOs). RNA and whole genome sequencing was performed from the original tumors and from PDOs. Pluripotency and proliferation were assessed via high-throughput immunofluorescent detection of PAX8 and Ki67. Resistance towards standard treatment and response to additional selected drugs and drug combinations were evaluated in cell death and proliferation assays. Imaging and image-based quantifications were performed under 3D setup. PDOs were set up for in vivo drug testing in immunodeficient NOD/Shi-scid/IL-2Rgnull (NOG) mice. Summary: A set of HGSC PDOs of different longitudinal, prospective, and multiregional samples has been established representing the three evolutionary states of HGSC: evolving, maintaining and adaptive state. They are ready to be used as rational and effective models for studying drug interventions. Supportively, results of preclinical studies with PI3K inhibitor Alpelisib matched the published patient responses. Tumor evolutionary analysis based on data of longitudinal, prospective, and multiregional collected samples suggest further targetable pathways that can mediate chemotherapy resistance and pinpoint potential targets for drug intervention. Conclusion: Inhibition of these pathways with simultaneous targeting of other cellular functions, such as lysosomal-mediated cell death, may be highly effective alternative treatment option. 3D imaging and efficient image analysis are necessary tools to understand tumor organoid biology and drug responses to assist development and pre-clinical evaluation of new treatments. This study is a part of the DECIDER project (https://www.deciderproject.eu/, NCT04846933). Citation Format: Tuula Kallunki, Anna R. Lauridsen, Aikaterini Skorda, Alexandra Lahtinen, Marie L. Bay, Benita Rasmussen, Kaisa Huhtinen, Taru Muranen, Jaana Oikkonen, Johanna Hynninen, Sampsa Hautaniemi. Establishment and analysis of patient-derived high-grade serous ovarian cancer organoids for disease modeling and drug testing [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 4249.