Progestin Therapy for Endometrial Cancer
Abstract
This Translational Team Science Award application addresses the fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of endometrial cancer, a new Topic Area for this award mechanism. The endometrium is the lining of the uterus and a highly hormone-responsive tissue. The steroid hormone estrogen causes the endometrium to grow in anticipation of a potential pregnancy, whereas progesterone, another steroid hormone, impedes estrogen-driven growth and causes the endometrium to mature further to support the embryo. Women with normal menstrual cycles rarely develop endometrial cancer; hence, endometrial cancer is a disease that mostly occurs after menopause or in premenopausal women with excess estrogen caused by disorders such as polycystic ovarian syndrome and obesity. In line with the obesity epidemic in the United States, endometrial cancer is also on the rise, both in incidence and death. To counter the excess estrogen, many women with endometrial cancer are prescribed synthetic progesterones, termed progestins. While most patients initially respond to treatment, recurrence is common at up to 40%. In addition, although there are now over 20 progestins that are U.S. Food and Drug Administration-approved for other indications (e.g., contraception, hormone replacement therapy), the most commonly prescribed progestin for endometrial cancer (medroxyprogesterone acetate - Depo-Provera) was discovered over 60 years ago. Its continued use is not necessarily because it is the most effective progestin; rather, it is because the others have not been evaluated for effectiveness in treating endometrial cancer. Another roadblock in broader progestin use for endometrial cancer is the lack of adequate ways to predict if a patient is likely to relapse. This project will identify a molecular signature that can be used on pretreatment tumor samples to predict if a patient will respond to progestin therapy. A behavioral survey will determine the impact of progestins on mood. Next, we will undertake a comprehensive mechanistic analysis of why some patients respond and others do not, with the goal of using this information to define new treatment approaches. Finally, we will use state-of-the-art patient-derived endometrial cancer model systems to compare head-to-head the full array of progestins used for other indications. This work will include both drug effectiveness and safety studies motivated by population studies that suggest progestins used for contraception or hormone replacement therapy increase the risk of breast cancer and have other vascular side effects, causing women to be reluctant to take hormonal therapy for endometrial cancer (and other indications). This project will yield the first molecular test to determine if a patient with a new diagnosis of endometrial cancer or its precursor disease, atypical endometrial hyperplasia, is a good candidate for progestin therapy or if they should consider complete hysterectomy instead. This project also has the potential to identify a safer and more effective hormonal therapy regimen that does not have adverse effects in other hormone-responsive tissues, like the breast. Having a safer and more effective hormone-based therapy will alleviate concerns in patients related to how the current cancer treatment may increase their chance of other cancers in the future. The FY22 PRCRP Overarching Challenges addressed by this application are to identify strategies to predict treatment resistance, recurrence, and the development of advanced disease though personalized hormonal therapy treatment of endometrial cancer patients. Our approach will combine techniques and several patient groups and samples to determine which patients are most likely to respond to progestin treatment and to identify progestins with the best efficacy and safety profile. Our study also includes an emotional well-being assessment of women who received progestins as treatment for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310744
Entities
People
- Kristina W. Thiel
Organizations
- United States Army
- University of Iowa