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Repurposing progestins to improve efficacy of hormone therapy for endometrial cancer
Abstract   Peer reviewed

Repurposing progestins to improve efficacy of hormone therapy for endometrial cancer

Kaitriana Colling, Abby Morrison, Emily Kolpin, Hiruni Sumanasiri, Danielle Uhl, Craig Rush, Jay Gertz, Miles Pufall, Christy Hagan, Kimberly Leslie, …
Gynecologic oncology, Vol.208(Supplement), pp.S53-S54
05/2026
DOI: 10.1016/j.ygyno.2026.01.085

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Abstract

Objectives Endometrial cancer is the most common gynecologic malignancy and recently surpassed ovarian cancer as the leading cause of mortality among gynecologic cancers. Progestin therapy has served as the only fertility-sparing intervention for endometrial cancer since the 1970s. Although up to 70% of patients initially respond to progestin therapy, ~40% of patients experience disease recurrence, highlighting a critical need for more effective hormone therapies. While only three progestins are used clinically for endometrial cancer, over 20 progestins are routinely used for other indications, including contraception and menopausal hormone therapy. Our objective was to systemically evaluate the effects of a broad panel of FDA-approved progestins in patient-derived organoid (PDO) models of endometrial cancer in order to identify candidates with greater efficacy as compared to the standard of care progestins. Methods Using our extensive biorepository of endometrial cancer PDOs, we tested a panel of 12 progestins in 12 independent treatment-naïve PDO models of early stage/grade endometrial cancer, representative of cases that could be managed non-surgically. PDO models were binned into TCGA molecular categories using whole exome sequencing. Assessment of drug response in PDO models was conducted using automated multiplexed live-cell imaging. Effects on growth and apoptosis were calculated based on PDO area and annexin V staining, respectively, over a range of doses for up to 5 days. Changes in growth and apoptosis were benchmarked against medroxyprogesterone acetate (MPA). Results In the study cohort, 15% of PDO models were categorized as MSI-H/MMRd and the remaining 85% as p53 wild type/NSMP, consistent with the expected molecular distribution of early stage/grade endometrial cancer. Our study revealed remarkable differences in the effects of progestins on growth and apoptosis in PDO models of endometrial cancer. First, MPA had variable effects on cell growth and apoptosis across different models, with some exhibiting sensitivity and others resistance. Next, several progestins achieved superior growth inhibition and apoptosis induction as compared to MPA. Notably, three different testosterone-derived progestins consistently outperformed MPA in the majority of PDO models. Progestin-mediated growth inhibition did not correlate with apoptosis for some agents, suggesting heterogeneity in mechanisms of progestin activity. Conclusions To our knowledge, this is the first comprehensive evaluation of the efficacy FDA-approved progestins in patient-derived preclinical models of endometrial cancer. Our study revealed that select progestins outperform the standard of care (MPA) in vitro. These findings support the feasibility of repurposing clinically available progestins as a safe and effective option for the conservative management of endometrial cancer. Future directions include identifying biomarkers of response and mechanisms of resistance and advancing top candidates into clinical trials.

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