Evaluating promising progestins through surgical window trials in women newly diagnosed with endometrial cancer

Project 4. Evaluate Promising Progestins in Endometrial Cancer Through a Rotating Umbrella Surgical Window Trial Abstract Progestins are the most commonly employed hormonal agents to treat and to prevent endometrial cancer and atypical endometrial hyperplasia (EC-AEH). There is a critical need to improve hormone therapy for EC- AEH given the substantial increase in incidence and mortality associated with this common malignancy and the increased lifetime risk of breast cancer associated with progestins in current use. In addition, there are more than 20 progestins routinely prescribed for contraception and hormone replacement therapy, but few have been evaluated for efficacy in the EC-AEH. The overall goal of this project is to test promising progestins in the clinical setting in order to identify better treatment strategies for EC-AEH patients. We will employ an innovative clinical trial platform paired with in depth molecular analyses of clinical samples to identify an improved “next generation” hormone treatment as well as biomarkers of response in two aims: Aim 1. Perform an adaptive, master protocol, surgical window of opportunity rotating umbrella trial to assess the effectiveness of progestins in tissues from women with newly diagnosed endometrial cancer or atypical endometrial hyperplasia. Substantial population- based data from the Women’s Health Initiative and other sources indicate that medroxyprogesterone acetate (MPA), commonly used in previous cooperative group trials, is not the ideal compound for women with EC-AEH. Although MPA is effective in the initial treatment of approximately 60% of EC-AEH patients, it is potentially an agonist with respect to breast epithelial proliferation and has been associated with an increased risk of breast cancer. We hypothesize that the most efficacious and safe progestin is one that inhibits cellular proliferation in gynecologic epithelia and does not induce proliferation in breast epithelia. We will rotate additional FDA- approved or commonly used progestins into the umbrella trial based upon preclinical data from Projects 1, 2, and 3 demonstrating effectiveness in inhibiting EC-AEH cancer models while not inducing proliferation in breast models. Aim 2. Establish biomarkers and molecular signatures of progestin efficacy in patients with endometrial cancer. We hypothesize that protein and gene expression patterns from patient specimens will reveal biomarkers of progestin efficacy. We will identify expression biomarkers predictive of outcome by RNA-seq using pre- treatment surgical samples and markers of efficacy by comparing pre- and post-treatment surgical samples from the window trial in Aim 1 in combination with additional patient samples and models that we have collected. We will also viably isolate tissue from hysterectomy specimens from patients on the trial in Aim 1 and collaborate with Project 1 to create and test organoids for progestin activity. The expected outcome of these studies is to confirm the effectiveness of one or more progestins identified from Projects 1, 2, and 3 in a novel clinical trial in women with EC-AEH. We will study only those compounds that show a strong response in the endometrium without increasing breast cancer development in preclinical models. We will also determine the best biomarkers of cellular response as well as the most efficacious agent to study in a future clinical trial.