The pharmacological actions of antiprogestins in uterine fibroids

抗孕激素治疗子宫肌瘤的药理作用

• 批准号: 7504946
• 负责人: Donald P McDonnell
• 金额: $ 40.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7504946
• 关键词: Acute; Adverse effects; Agonist; Androgen Receptor; Biological; Biology; Cell model; Cells; Characteristics; Chronic; Clinical; Clinical Research; Complex; Development; Dilatation - action; Disease; Drug Delivery Systems; Endometrial; Endometrium; Estrogen Antagonists; Estrogen Receptor Modulators; Evaluation; Fibroid Tumor; Gene Expression; Genes; Gland; Hemorrhage; Intervention; Investigation; Laboratories; Lead; Learning; Ligands; Longitudinal Studies; Mediating; Medical; Modality; Modeling; Molecular Mechanisms of Action; Nuclear Receptors; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Pelvis; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Placebos; Pre-Clinical Model; Process; Progesterone; Progesterone Receptors; Progestins; Relative (related person); Role; Series; Structure; System; Technology; Testing; Therapeutic; Tissues; Translating; Uterine Fibroids; Validation; Work; base; cancer therapy; cell growth; cofactor; disease phenotype; drug discovery; genetic regulatory protein; improved; insight; malignant breast neoplasm; myometrium; novel; novel strategies; pressure; receptor; response; tumor

The therapeutic utility of inhibiting/modulating progesterone receptor (PR) transcriptional activity in uterine fibroids has been well validated both in preclinical models of this disease and in several definitive clinical studies. Indeed, both antiprogestins and Selective Progesterone Receptor Modulators (SPRMs) have been shown to reduce fibroid volume, control bleeding and reduce pelvic pressure. Unfortunately, whereas acute responses in fibroids to both classes of PR modulators have been favorable in terms of efficacy and general side effect profile, they also induce distinct endometrial changes that are characterized by asynchrony between endometrial glands and stroma with occasional cystic dilatation of these same glands. Although the clinical consequences of these unexpected endometrial responses are unclear, they have emerged as an impediment to the use of antiprogestins and SPRMs for all but short-term use as treatments for fibroids. Although it is unlikely that the long-term studies required to justify chronic administration of the currently available antiprogestins/SPRMs will be performed, the fact remains that PR is the best-validated drug target for extended treatment of this disease. Given the importance of this clinical problem and the unmet need for medical interventions that either mitigate the symptomatic presentation of the disease or improve surgical outcomes, it is our opinion that a mechanism-based approach toward PR modulator discovery may yield drugs with improved pharmaceutical profiles. From our studies of the mechanism of action of nuclear receptor (NR) pharmacology over the past few years, we have learned that the relative agonist/antagonist activity of specific receptor modulators is determined by (a) the impact of ligands on the structure of the receptor, (b) the differential interaction of cofactors1 with differently conformed NR-ligand complexes, and (c) the relative expression level and activity of relevant cofactors in target cells. We have exploited this concept to develop several new classes of functionally distinct androgen receptor (AR) modulators for the treatment of cancer and other androgenopathies and a new antiestrogen that is currently being evaluated in patients with metastatic breast cancer. Similarly, we propose to evaluate the role(s) of specific coactivators and corepressors in mediating the biological responses to progestins and antiprogestins in cellular models of uterine fibroids and relate these findings to the biology of fibroids. These studies will provide basic insights into the molecular mechanisms of action of progestins and antiprogestins that are likely to translate to other systems. However, we also anticipate that this investigation will lead to development and validation of new approaches with which to identify novel antiprogestins/SPRMs that effectively treat fibroids but which do not manifest abnormal pathological responses in the endometrium.

抑制/调节孕酮受体（PR）转录活性的治疗效用 子宫肌瘤在该疾病的临床前模型中都得到了很好的验证 确定的临床研究。实际上，抗膜蛋白和选择性孕酮受体 调节剂（SPRMS）已显示可减少肌瘤的体积，控制出血并减少骨盆 压力。不幸的是，尽管肌瘤中对这两类PR调节剂的急性反应具有 在功效和一般副作用概况方面都很有利，它们也引起了不同的 子宫内膜变化的特征是子宫内膜腺与基质之间的异步变化 这些相同的腺体偶尔进行囊性扩张。虽然这些临床后果 意外的子宫内膜反应尚不清楚，它们已成为使用 除短期用作肌瘤的治疗外，抗植物和SPRMS和SPRMS。虽然不太可能 长期的研究需要证明当前可用的长期管理是合理的 将进行抗植物/SPRMS，事实仍然是，PR是验证最佳的药物靶标 该疾病的扩展治疗。考虑到这个临床问题的重要性和未满足的需求 对于减轻疾病症状表现或改善的医疗干预措施 手术结果，我们认为是基于机制的PR调节器的方法 发现可能会产生具有改善药物特征的药物。从我们对 在过去的几年中，核受体（NR）药理学的作用机理，我们有 得知特定受体调节剂的相对激动剂/拮抗剂的活性取决于 （a）配体对受体结构的影响，（b）辅因子的差异相互作用1 具有不同符合的NR配体复合物，以及（c）相对表达水平和活性 靶细胞中的相关辅因子。我们已经利用了这个概念来开发几个新类 功能上不同的雄激素受体（AR）调节剂用于治疗癌症和其他 雄激素病和一种新的抗雌激素，目前正在转移患者中评估 乳腺癌。同样，我们建议评估特定的共激活因子和核压剂的作用 在介导子宫细胞模型中孕激素和抗植物的生物学反应时 肌瘤并将这些发现与肌瘤的生物学联系起来。这些研究将提供基本的见解 进入可能转化为孕激素和抗膜蛋白作用的分子机制 其他系统。但是，我们还预计，这项调查将导致发展和 验证新方法以识别有效治疗的新型抗树脂蛋白/SPRM 肌瘤，但没有表现出子宫内膜中异常的病理反应。