Safety and Molecular Mechanisms of CDB-2914

CDB-2914的安全性和分子机制

• 批准号: 7284735
• 负责人: PATRICIA L. MORRIS
• 金额: $ 37.98万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284735
• 关键词: Affect; Agonist; Androgen Receptor; Androgens; Applications Grants; Biopsy; Breast; Breast Diseases; CDB 2914; Cell Cycle; Cell Cycle Kinetics; Cell Line; Cell model; Cell physiology; Cells; Characteristics; Class; Clinical; Clinical Research; Clinical Trials; Combined Oral Contraceptives; Conceptions; Contraceptive Agents; Contraceptive methods; Cytoplasmic and Nuclear Receptors; Development; Dose; Duct (organ) structure; Endometrial; Endometrial Carcinoma; Endometrium; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Estrogen Receptor beta; Estrogens; Evaluation; Exposure to; Feasibility Studies; Flow Cytometry; Gene Expression; Genes; Goals; Growth; Growth Factor; Health; Healthcare; Hemorrhage; High Risk Woman; Histology; Hormone replacement therapy; Hormones; Human; Incidence; Intrauterine Devices; Investigation; Ligands; Malignant Epithelial Cell; Mammary Gland Parenchyma; Mammary Tumorigenesis; Mammary gland; Measures; Medroxyprogesterone 17-Acetate; Modeling; Molecular; Molecular Models; Mus; Muscle Cells; Myoma; Myometrial; Normal tissue morphology; Oral Contraceptives; Ovulation; Pattern; Phase; Phase II Clinical Trials; Physiological; Population; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Prevention; Progesterone; Progesterone Receptors; Progestins; Progress Reports; Proliferating; Proliferation Marker; Protein Isoforms; Proteomics; Publishing; Range; Rattus; Reproductive Health; Research; Role; Safety; Serum; Small Interfering RNA; Stanolone; Stem cells; Steroid Receptors; Steroids; Synthetic Progestogens; System; Thick; Time; Tissue Sample; Tissues; Uterine Fibroids; Vaginal Ring; Vascular Endothelial Growth Factors; Vascularization; Week; Woman; cancer cell; cancer risk; clinical application; concept; cytokine; day; emergency contraception; endometriosis; hormone therapy; in vivo; malignant breast neoplasm; molecular modeling; prevent; receptor; receptor expression; reproductive; research clinical testing; response; stem; tumor

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.

项目III：选择性孕酮受体调节剂（SPRMS）代表新的孕酮类 从完整的PR拮抗剂到具有混合激动剂/拮抗剂的化合物的受体（PR）配体 体内各种孕酮靶组织的活性。由于对PR的不同影响，特定的PRM是 正在研究生殖卫生保健中的多个临床应用。潜在的临床应用 SPRMS的包括紧急避孕，长期无雌激素避孕和绝经后 激素疗法以及肌瘤，子宫内膜异位症和激素依赖性肿瘤的治疗。这 拟议的研究结合了分子建模，翻译和临床研究，以进一步研究 CDB-2914的临床安全性并表征其在细胞水平上对激素靶组织的影响。目标1： 使用原发性建立和表征正常人乳腺上皮细胞（HMEC）的反应 培养模型至：a）确定短期和长期暴露后细胞周期动力学的特征 CDB-2914，在E2和/或P4的存在下； b）确定茎和 祖细胞可以分离以进一步研究，以建立CDB-2914在乳房上的长期安全性 干细胞。 AIM 2：建立和表征小鼠乳腺茎和祖细胞群体为EX 研究CDB-2914对乳房的影响的体内模型，研究了类固醇受体表达的研究 和功能。使用PRM开发长期无雌激素的避孕措施，这也将防止P 对乳房的作用可能是一种具有双重好处的避孕方法，即预防受孕 和乳房疾病。关于PRM的子宫内膜作用的新发现证明了进一步的临床评估。目标3： 第一项临床研究将探索从阴道环上传递的CDB 2914的子宫内膜作用 剂量阻断排卵。子宫内膜组织学和增殖标记将随着时间的流逝而确定。一个 第二个临床研究将评估12周PRM环后的顺序2周孕激素课程是否 将扭转任何子宫内膜变化。第三项临床研究将评估低剂量CDB-的影响 2914使用宫内系统应用于正常排卵的同时仅诱导局部效应 维护。 AIM 4：建立人子宫内膜上皮细胞（HEEC）模型 与CDB-2914和SPRMS对孕激素作用的研究和表征 子宫内膜：a）确定存在或不存在雌激素时细胞周期相关的作用，比较 孕激素的活性（P4； Medroxyprogesterone，MPA）与CDB-2914的活性使用几种 永生的人子宫内膜癌细胞； b）比较Sprms，孕激素，雌激素或 使用基因表达和蛋白质组学分析，对HEEC功能的顺序激素暴露。项目 III结合了基本，转化和临床研究，以进一步确定CDB-2914对人的安全性 使用该PRM分子机制的使用以及表征。