Project III: Selective Progesterone Receptor Modulators (SPRMs) represent a new class of progesteronereceptor (PR) ligands that range from full PR antagonists to compounds with mixed agonist/antagonistactivities on various progesterone target tissues in vivo. Due to diverse effects on the PR, specific PRMs arebeing investigated for multiple clinical applications in reproductive health care. Potential clinical applicationsof SPRMs include emergency contraception, long-term estrogen-free contraception and post-menopausalhormone therapy, and treatments for myomas, endometriosis and hormone-dependent tumors. Theproposed studies combine molecular modeling, translational, and clinical studies to further investigate theclinical 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 primaryculture models to: a) Determine characteristics of cell cycle kinetics after short and long term exposure toCDB-2914, in the presence of E2 and/or P4; b) Determine whether a proliferating population of stem andprogenitor cells can be isolated for further study ex vivo to establish long-term safety of CDB-2914 on breaststem cells.
Aim 2 : Establish and characterize mouse mammary stem and progenitor cell populations as exvivo models to study effects of CDB-2914 on the breast, studies with a focus on steroid receptor expressionand function. Developing a long-term estrogen-free contraception using a PRM that would also prevent Paction on the breast is potentially a contraceptive method with dual benefits, i.e., prevention of conceptionand 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 adose blocking ovulation. Endometrial histology and proliferation markers will be determined over time. Asecond clinical study will evaluate whether sequential 2-week progestin courses after 12-week PRM ring usewill 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 ismaintained.
Aim 4 : Establish a human endometrial epithelial cell (HEEC) model for molecular modelingstudies and characterization of the effects of progestins compared to those of CDB-2914 and SPRMs on theendometrium: a) Determine cell cycle-related effects when estrogen is present or absent, comparing theactivity of progestins (P4; medroxyprogesterone acetate, MPA) with that of CDB-2914 using severalimmortalized human endometrial carcinoma cells; b) Compare effects of SPRMs, progestin, estrogen, orsequential hormone exposure on HEEC functions, using gene expression and proteomic analyses. ProjectIII combines basic, translational and clinical studies to further ascertain the safety of CDB-2914 for humanuse as well as characterization of this PRM's molecular mechanisms.
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