Abstract B008: Modeling radiation sensitivity in patient-derived organoid models of endometrial cancer

Abstract

Abstract Endometrial cancer is the 4th most common cancer in women, with increasing incidence and deaths each year from 2008 to 2017. The typical treatment for high grade and advanced endometrial cancer includes cytoreductive surgery followed by radiation and/or chemotherapy, depending on stage, grade, and other risk factors. Despite advances in molecular classification of endometrial cancer, there is a paucity of data on the mechanisms of sensitivity and resistance to radiation and chemotherapy. One reason for this lack of understanding is because, clinically, surgery is not typically offered in the setting of recurrence; thus, there are no available specimens to assess how the tumor evolves in response to therapy. Preclinical models can in part overcome this roadblock, yet there are very few preclinical models of endometrial cancer that accurately recapitulate the heterogeneity of human disease. Our objective was to define how endometrial tumors respond to radiation and chemotherapy using patient-derived organoid models. First, we have established a living biorepository that includes over 30 patient-derived organoid models of high risk or advanced endometrial cancer, with available clinical response data. Specifically, tumor specimens were obtained at the time of primary surgery and digested to generate single cell suspensions, which were then resuspended in basement membrane extract (BME), plated as three-dimensional domes, and cultured in specialized media. Organoids with a diameter of >50 µm typically formed in 48-96 hours after initial plating. For therapeutic studies, organoids were plated as BME domes in 96-well plates, followed by exposure to increasing levels of radiation (2-16 Gy) and/or chemotherapy (carboplatin+paclitaxel, 10 nM – 10 µM). Drug effects were monitored using an automated kinetic live-cell imaging platform (Cytation5) in which media was supplemented with fluorescent dyes to multiplex interrogation of cell health and induction of apoptosis. To date, we have observed differential sensitivity to radiation and chemotherapy in patient-derived organoid models of high risk and advanced endometrial cancer as determined by changes in organoid number and size and induction of apoptosis. These studies are the first to examine the therapeutic effects of radiation in endometrial cancer patient-derived organoid models. Ongoing studies are correlating response to therapy in patient-derived organoid models with clinical patient outcomes. We are also performing pre- and post-treatment transcriptomic analyses to define gene signatures of response to radiation and cytotoxic chemotherapy in endometrial cancer organoid models. The ultimate goal is to use these heterogeneous preclinical models to identify pretreatment biomarkers of response that can be translated to a clinical diagnostic test. Citation Format: Sofia Gabrilovich, Kaitriana Powell-Smith, Hiruni Sumanasiri, Emily Symons, Emily Hill, Miles Pufall, Donna Santillan, Kristina W. Thiel. Modeling radiation sensitivity in patient-derived organoid models of endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B008.