Abstract 40: Organoid models of ovarian clear cell carcinoma for evaluating therapeutic sensitivity

Ovarian clear cell carcinoma (OCCC) is a rare subtype of ovarian cancer, often resistant to platinum-based chemotherapy. OCCC is characterized by ARID1A mutations, PI3K and RAS/MAPK pathway alterations, and activation of the HIF signaling pathway. We and others showed that OCCC are sensitive to inhibition of BCL-XL, a pro-survival protein in the intrinsic pathway of apoptosis. Patient-derived models of OCCC could potentially accelerate pre-clinical testing of therapeutics in this difficult-to-treat cancer, but relatively few patient-derived organoid (PDO) or xenograft models of OCCC have been reported. We describe the establishment and propagation of two PDO models of OCCC. Patient 1 had recurrent OCCC with PIK3CA mutation and HER2 amplification. Patient 2 had recurrent OCCC with CDKN2A/B deletion. Both patients underwent secondary cytoreductive surgery for recurrent disease. Fresh tissue was collected under IRB-approved protocols and tumor cells were plated in Matrigel and formed PDOs. Patient 1 OCCC cells have been propagated for over 35 passages, and patient 2 cells for 9 passages to date. Immunohistochemistry to confirm fidelity to the original tumor is in progress. As a proof-of-concept for evaluating therapeutics in OCCC PDOs, we used a 3D microfluidic device (AIM Biotech) to evaluate drug responses in patient 1 PDO. PDO cells were seeded in the microfluidic device and expanded for one week, treated with drugs within the device, then stained at day 6 with fluorescence markers for live (TMRM, Thermo Fisher), apoptotic (CellEvent Caspase-3/7, Thermo Fisher), and dead (DRAQ7, CST) cells. Quantitative imaging was performed to determine the cell area positive for each marker. The OCCC PDO was treated with standard-of-care chemotherapies carboplatin and paclitaxel; BCL-XL inhibitor A1331852 (Selleckchem); a novel BCL-XL PROTAC degrader DT2216 (Dialectic Therapeutics); or combinations of the BCL-XL inhibitor/degrader with paclitaxel. Treatment with A1331852 or DT2216 induced apoptosis and death in the OCCC PDO cells compared to control. While paclitaxel alone also induced some cell death, the combination of DT2216 (1µM) and paclitaxel (500nM) was highly potent, resulting in elimination of almost all the OCCC cells (Bliss synergy score 0.28±0.08, p=0.013). These data suggest that BCL-XL inhibition/degradation combined with paclitaxel may be a promising treatment strategy for OCCC. Our study also demonstrates the successful establishment of OCCC PDOs and application of a microfluidic device for evaluating novel therapeutic strategies in ovarian cancer. Citation Format: Clare E. Padrick, Magdalena Zielinska, Minh Ha, Aisha L. Saldanha, Cam Anh Tran, Brendan Shay, Daohong Zhou, Kristopher A. Sarosiek, Cloud P. Paweletz, Ursula A. Matulonis, Joyce F. Liu, Elena V. Ivanova, Elizabeth H. Stover. Organoid models of ovarian clear cell carcinoma for evaluating therapeutic sensitivity [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 40.