Abstract B027: Screening of drug candidates to repurpose for high-grade serous ovarian cancer treatment

Abstract Introduction: Ovarian cancer (OVC) is the most lethal gynecological cancer. The 5-year survival rate of OVC in Europe is 47% and in Denmark it is only 41%, indicating need for identifying novel efficient treatments. More than 75% of ovarian cancers are characterized as high-grade serous ovarian cancer (HGSC), and almost all HGSC patients experience recurrence and development of platinum-taxane treatment resistance. Here we established a drug screening and evaluation platform using HGSC cell lines and patient organoid samples in 3D cultures for testing drugs approved for treatment of different types of cancer and other diseases. Materials and methods: The drugs tested in this project have been selected according to screenings of the NCI Approved Oncology Drugs library and the Prestwick chemical library® on MCF7, LR-MT2, and SKOV3 cells, analyzing for change in lysosomal localization. The selected drugs were tested as monotherapy or in combination with carboplatin and paclitaxel, and drug responses in standard culture medium were compared to human plasma-like medium (PlasmaX™, XimBio). Drug responses were evaluated with two relatively platinum-resistant cell lines of HGSC representing different genetic backgrounds: OVSAHO and OVCAR3. In addition, promising drug candidates were tested on patient organoids, which were established from tissues collected from OVC patients and grown as 3-dimensional (3D) ex vivo long-term tumor organoid cultures as part of the DECIDER project (https: //www. deciderproject. eu/, NCT04846933). Invasive growth and cell death was assessed by high-throughput imaging using the ImageXpress Confocal microscope (Molecular Devices). Image analysis was performed using MetaXpress software. Viable and reliable xenotransplant models of OVSAHO and OVCAR3 were established by rederiving the original cell lines (Permission no: 2018-15-0201-01391). Results: This screening identified several interesting drug candidates from both the NCI Approved Oncology Drugs library and the Prestwick chemical library® that show promising induction of cell death and/or inhibition of growth. Most promising was an anti-inflammatory agent, which induced more than 80% cell death in the OVSAHO cell line at a concentration of 5 uM. Interestingly, some drugs induced significantly different responses in human plasma-like medium (HPLM) compared to the standard culture medium, while others were not affected, and some drugs also showed interaction with carboplatin and/or paclitaxel. Mouse models of xenotransplants have been established for future experiments. Conclusion: We have identified promising drug candidates that could serve as alternative treatment for platinum-resistant HGSC. This study is supported by Fabrikant Chas. Otzen´s Fond, Købmand Niels Erik Munk Pedersen Fonden, and by the Horizon2020 project DECIDER (grant no. 965193). Citation Format: Marie L. Bay, Aikaterini Skorda, Benita S. Rasmussen, Jaume R. Arias, Anna R. Lauridsen, Kaisa Huhtinen, Sampsa Hautaniemi, Johanna Hynninen, Tuula Kallunki. Screening of drug candidates to repurpose for high-grade serous ovarian cancer treatment 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 B027.