Preclinical efficacy of progestins in endometrial cancer

University Of New Mexico Health Scis Ctr, Albuquerque NM

Investigators

Abstract

PROJECT 1 SUMMARY / ABSTRACT: Efficacy of Progestins in Preclinical Models of Endometrial Cancer Uterine endometrial cancer (EC) incidence and mortality are on the rise worldwide. Deaths due to EC recently overtook ovarian cancer, which makes EC the deadliest gynecologic cancer. Surgery is the frontline treatment for EC, followed by surveillance or adjuvant chemotherapy/radiation. Surgery alone has historically been curative for patients with differentiated endometrioid EC and also the precursor lesion, atypical endometrial hyperplasia (AEH), which is a major health concern due to its high rate of progression to EC. However, the obesity epidemic is accompanied by an increasing number of patients with medically complex comorbidities that limit surgical options. Furthermore, surgery includes complete hysterectomy, which is a significant concern for patients who desire childbearing. Therefore, there is a critical need for better conservative non-surgical management strategies that can effectively prevent the transition of AEH to EC as well as prevent progression of EC. Hormonal therapy with synthetic progesterone mimics, termed progestins, is currently the only viable non-surgical approach and only pharmacological agent FDA-approved for the treatment of primary EC-AEH. Nearly 75% of patients initially respond to progestin therapy, yet up to 40% of these patients later recur. Hence, the currently used progestins have only moderate efficacy in controlling EC-AEH, suggesting that studies are necessary to identify progestins that produce a sustained response and overcome resistance. Our objectives are to 1) establish the preclinical efficacy of repurposed progestins in EC; and 2) identify new opportunities to achieve a more durable progestin response and identify agents that can overcome resistance. In Aim 1, we will determine the efficacy of progestins to decrease proliferation, promote differentiation, induce apoptosis and blunt tumor growth in preclinical models of EC-AEH. Aim 2 will identify agents that potentiate the anti-proliferative effects of progestins and overcome resistance. The expected outcome for Project 1 is to identify clinically used progestins that promote tumor regression by blocking cancer cell proliferation and promoting differentiation. In addition, we will also discover combinatorial regimens to mitigate resistance and search for novel progestins for future clinical study. This work is anticipated to have a positive impact on the future treatment of EC-AEH by providing the first comprehensive comparison of different progestin agents using clinically relevant EC-AEH specimens from patients. Importantly, this project synergizes with the other P01 Projects both by providing key knowledge on the cellular consequences of progestins in the endometrium and incorporating insight (e.g., targets for combinatorial treatment) and specimens from other Projects.