Modeling Response to Progestin Therapy in Patient-Derived Organoid Models of Endometrial Cancer

Kaitriana Colling; Emily Kolpin; Abby Morrison; Hiruni Sumanasiri; Kristina W Thiel

doi:10.1210/endocr/bqaf043.013

Endometrial cancer (EC) is the most common gynecologic cancer and this year is anticipated to surpass ovarian cancer as the deadliest gynecologic malignancy in the United States. Although surgery is curative for EC when detected at an early stage, rates of the disease are rising amongst pre-menopausal, obese women, highlighting an urgent need for non-surgical treatment interventions. The only available fertility-sparing intervention for EC is treatment with progestins, which are pharmacologic agents that mimic the inhibitory effects of progesterone on endometrial proliferation. Although 75% of patients initially respond to progestins, the clinical benefit is limited in duration and 40% of patients ultimately recur. Out of over 20 progestins that have been FDA-approved for various purposes (e.g., hormonal contraception), only three are used clinically for the treatment of EC. Our objective is to repurpose existing progestins and identify next-generation agents with improved anti-tumor efficacy for EC treatment. Herein we employed highly translational patient-derived organoid (PDO) models of EC to perform the first side-by-side comparison of progestins in EC. First, we generated a biorepository of 40 early stage/grade EC PDOs in which patient tumor cells were grown in a 3D matrix. Next, we developed a novel method for multiplexed live-cell imaging that allows for simultaneous assessment of multiple cellular readouts over time, such as growth and apoptosis. To define the phenotypic effects of a panel of progestins, PDOs were exposed to progestins and non-perturbing live-cell dyes and then imaged over a period of 5-7 days. Specific parameters of interest within the PDO population were calculated (e.g., total organoid area, fluorescence intensity) and benchmarked against standard progestin therapies for EC. Preliminary studies in a subset of PDO models revealed that certain repurposed progestins are more efficacious at inhibiting growth and promoting apoptosis in PDOs compared to the gold standard medroxyprogesterone acetate. Ongoing studies are examining the effects of progestins in a broader panel of PDO models, along with evaluating safety using normal endometrial PDOs. The results of this study are anticipated to identify new progestins that can be advanced into clinical trials in the near future, with the ultimate goal of improving choice of hormone therapy for EC patients. Date of Presentation October 17, 2024

Modeling Response to Progestin Therapy in Patient-Derived Organoid Models of Endometrial Cancer

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