Targeting Progesterone Resistance for Endometrial Cancer Prevention - PROJECT SUMMARY/ABSTRACT Endometrial cancer (EC) is the only female cancer with rising incidence and mortality, especially among young women, in parallel with the obesity epidemic. Since most EC arises from the precancerous lesion, known as endometrial intraepithelial neoplasia (EIN or AEH), developing effective therapy for EIN offers a promising approach to prevent EC progression and reduce overall disease burden. Surgery is the standard therapy for early-stage EC and EIN but is inappropriate for young and obese women due to fertility loss and surgical complications. Although progesterone (PG) therapy provides a nonsurgical alternative for these patients, approximately 20-41% of these patients develop resistance due to the loss of progesterone receptors (PRs). Moreover, PG therapy can cause weight gain, and obesity itself is associated with poor PG responsiveness. Our preliminary studies demonstrated that PR loss in EC and EIN is significantly associated with dysregulated histone deacetylases (HDACs), particularly HDAC8, which modulates PR expression, downstream signaling, and PG sensitivity. We further demonstrated that sulforaphane (SFN), an agent known to regulate obesity and inhibit HDAC8, restores PR expression and enhances PG efficacy in preclinical models. Therefore, we hypothesized that inhibition of HDAC8 will enhance PG therapy efficacy and overcome long-term PG resistance by reactivating PR in the endometrium, providing an effective therapeutic alternative to treat EIN, specifically in obese, young, and progesterone-resistant patients. The main goal of this study is to reduce the risk of EC by preventing its development from EIN. The central hypothesis will be tested by pursuing three aims: 1) validate the role of HDAC8 in PG resistance, optimize combination dosing HDAC8 inhibitors and PG using a quantitative systems biology approach, and evaluate the efficacy of selected dosing regimens in PG-resistant EIN models; 2) evaluate the preventive and therapeutic efficacy of SFN and selected HDAC8 inhibitor in combination with PG in an obesity-associated EIN; and 3) conduct a randomized window of opportunity pilot study of medroxyprogesterone acetate (MPA) plus SFN in patients with EIN or early-stage endometrioid endometrial cancer, assessing effects on proliferation marker (Ki-67), histologic response, SFN-regulated pathways, and obesity-associated biomarkers. Overall, this project will evaluate the translational potential of HDAC8 inhibitors, including SFN, in combination with PG for EIN/EC patients. Prevention of EC development by treating EIN will provide a unique mechanism to preserve fertility and be more cost-effective than the current standard of care. Validated animal models that closely recapitulate human endometrial cancer are essential for generating efficacy, pharmacokinetics, toxicity, and mechanistic data that cannot be obtained through alternative approaches. Successful completion of this work is anticipated to improve the quality of life, specifically for obese and younger EC patients, given the limited treatment options available to them, and provide rationale for future clinical trials of HDAC8 inhibitors and SFN-based prevention strategies.
