Safety and Molecular Mechanisms of CDB-2914

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Project III: Selective Progesterone Receptor Modulators (SPRMs) represent a new class of progesterone receptor (PR) ligands that range from full PR antagonists to compounds with mixed agonist/antagonist activities on various progesterone target tissues in vivo. Due to diverse effects on the PR, specific PRMs are being investigated for multiple clinical applications in reproductive health care. Potential clinical applications of SPRMs include emergency contraception, long-term estrogen-free contraception and post-menopausal hormone therapy, and treatments for myomas, endometriosis and hormone-dependent tumors. The proposed studies combine molecular modeling, translational, and clinical studies to further investigate the clinical safety of CDB-2914 and characterize its effects at a cellular level on hormone target tissues. Aim 1: Establish and characterize responses of normal human mammary epithelial cells (HMEC) using primary culture models to: a) Determine characteristics of cell cycle kinetics after short and long term exposure to CDB-2914, in the presence of E2 and/or P4; b) Determine whether a proliferating population of stem and progenitor cells can be isolated for further study ex vivo to establish long-term safety of CDB-2914 on breast stem cells. Aim 2: Establish and characterize mouse mammary stem and progenitor cell populations as ex vivo models to study effects of CDB-2914 on the breast, studies with a focus on steroid receptor expression and function. Developing a long-term estrogen-free contraception using a PRM that would also prevent P action on the breast is potentially a contraceptive method with dual benefits, i.e., prevention of conception and breast disease. New findings on endometrial effects of PRMs justify further clinical evaluation. Aim 3: The first clinical study will explore the endometrial effects of CDB 2914 delivered from a vaginal ring at a dose blocking ovulation. Endometrial histology and proliferation markers will be determined over time. A second clinical study will evaluate whether sequential 2-week progestin courses after 12-week PRM ring use will reverse any endometrial changes. The third clinical study will evaluate the effects of low doses of CDB- 2914 applied using an intrauterine system to induce only a local effect while a normal ovulation is maintained. Aim 4: Establish a human endometrial epithelial cell (HEEC) model for molecular modeling studies and characterization of the effects of progestins compared to those of CDB-2914 and SPRMs on the endometrium: a) Determine cell cycle-related effects when estrogen is present or absent, comparing the activity of progestins (P4; medroxyprogesterone acetate, MPA) with that of CDB-2914 using several immortalized human endometrial carcinoma cells; b) Compare effects of SPRMs, progestin, estrogen, or sequential hormone exposure on HEEC functions, using gene expression and proteomic analyses. Project III combines basic, translational and clinical studies to further ascertain the safety of CDB-2914 for human use as well as characterization of this PRM's molecular mechanisms.