Abstract 1715: Novel patient-derived organoids (PDOs) models for studying HER2-positive endometrial cancer

Abstract Endometrial carcinoma (EC) is the most common cancer of the reproductive organs in women with 66, 200 new cases and 13, 030 deaths in United States in 2023. Recent clinical trials are evaluating the use of antibody-drug conjugates (ADCs), such as trastuzumab-deruxtecan (T-Dxd) for the treatment of solid tumors, including EC. T-Dxd consists of anti-HER2 antibody (trastuzumab) and topoisomerase I inhibitor (deruxtecan). The mechanism of action of T-Dxd involves the HER2-directed cytotoxic effect induced by deruxtecan, as well as the bystander killing effect when deruxtecan is released into neighboring cells. This dual mode of action makes T-Dxd a suitable candidate for the treatment of both HER2-high and HER2-low cancers. Patient-derived organoids (PDOs) have emerged as models for studying tumor biology and screening for new drugs. As opposed to regular 2D cultures, organoids provide a more accurate representation of the key features and therapeutic response of patient tumors. The primary goal of our project is to generate endometrial cancer PDOs to test the efficacy of new combination treatments including T-DXd. We have successfully generated several organoid lines from endometrioid and clear cell cancer tissues using patient samples obtained from surgeries. Established organoids were submitted for pathological review and genetic testing which demonstrated that tissue morphology and genetic alterations of PDOs strongly correlate with patient tumors. Immunohistochemical analysis has shown that T-DXd treatment of the organoids causes a decrease in HER2 levels and an increase in pERK1/2 levels. We also treated the HER2-positive organoids with the combination of T-DXd and MEK inhibitors and monitored changes in growth. We observed decreased growth of organoids after combination treatment compared to untreated control. In conclusion, we successfully generated PDOs models of endometrial tumors and confirmed the response to single-agent and combination treatments. Obtained organoid lines can be further utilized to study tumor biology and test new combinations of drugs. Citation Format: Natalia Bednarek, Anh Q. Nguyen, Julieta Barroeta, Benedikt Nagele, Subin Myong, Katherine Kurnit, Diane Yamada, Gini Fleming, Sridevi Challa. Novel patient-derived organoids (PDOs) models for studying HER2-positive endometrial cancer [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 1715.