Enhancing Progestin Therapy with a Glucagon-Like Peptide 1 Agonist for the Conservative Management of Endometrial Cancer.

OBJECTIVE: Obesity is a major risk factor for endometrial cancer. In addition to hormone therapy with progestins, glucagon like peptide-1 receptor (GLP-1R) agonists such as semaglutide may be helpful to achieve weight loss during conservative treatment of endometrial hyperplasia or cancer. METHODS: We theorized that the combination of semaglutide and the progestin levonorgestrel would be useful as a novel treatment or prevention regimen and tested this hypothesis using endometrial cancer cell lines and patient-derived organoids (PDOs). RESULTS: Hec50, KLE, and Ishikawa endometrial cancer cells express GLP-1R, as determined by both qPCR and Western blotting, and GLP-1R agonist treatment induces GLP-1R mRNA transcription through positive feedback mechanisms in cell models. PDOs from six individuals with grade 1 endometrial carcinomas were treated with progesterone, levonorgestrel, semaglutide, or levonorgestrel + semaglutide. Multiple models demonstrated a significant reduction in viability in response to combinatorial treatment, and the effect was noted in models from both PR high- and PR low-expressing tumors. Most interesting was the induction not only of the membrane GLP-1R with treatment, but also the significant upregulation of nuclear and membrane progesterone receptors-PR and PGRMC1/2, respectively-indicating a potential positive feedback loop between semaglutide and progestins such as levonorgestrel. CONCLUSION: In summary, we identify synergistic molecular cross-talk between the GLP-1R and steroid hormone receptor pathways, with the potential to enhance the anticancer activity of levonorgestrel when combined with semaglutide.