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/调节孕激素受体（PR）转录活性的治疗效用 子宫肌瘤已经在这种疾病的临床前模型和几个临床模型中得到了很好的验证。 明确的临床研究。事实上，抗孕激素和选择性孕激素受体 调节剂（SPRM）已被证明可以减少纤维瘤体积，控制出血并减少盆腔炎。 压力不幸的是，尽管肌瘤对两类PR调节剂的急性反应都有 在功效和一般副作用方面是有利的，它们还诱导明显的 以子宫内膜腺体和间质之间的粘连为特征的子宫内膜变化 这些腺体偶尔会出现囊状扩张尽管这些的临床后果 意外的子宫内膜反应尚不清楚，它们已成为使用 抗孕激素和SPRM用于除短期外的所有肌瘤治疗。虽然不太可能 需要长期研究来证明目前可用的 虽然将进行抗孕激素/SPRM，但事实仍然是PR是最有效的药物靶点， 这种疾病的长期治疗。鉴于这一临床问题的重要性和未满足的需求 用于减轻疾病症状表现或改善 手术结果，这是我们的意见，一个机制为基础的方法对PR调节剂 发现可以产生具有改进的药物特性的药物。从我们对 核受体（NR）药理学的作用机制在过去的几年里，我们已经 了解到特定受体调节剂的相对激动剂/拮抗剂活性由以下决定： (a)配体对受体结构的影响，（B）辅因子1的差异相互作用 与不同构象的NR-配体复合物，和（c）相对表达水平和活性， 靶细胞中的相关辅因子。我们利用这一概念开发了几种新的 用于治疗癌症和其他疾病的功能不同的雄激素受体（AR）调节剂 雄激素病和一种新的抗雌激素，目前正在评估患者转移 乳腺癌同样，我们建议评估特定的辅激活因子和辅抑制因子的作用 在子宫内膜癌细胞模型中介导对孕激素和抗孕激素的生物反应 并将这些发现与纤维瘤的生物学联系起来。这些研究将提供基本的见解 孕激素和抗孕激素的分子作用机制可能会转化为 其他系统。然而，我们也预计，这项调查将导致发展， 验证新方法，以确定有效治疗的新型抗孕激素/SPRM 纤维瘤，但在子宫内膜中不表现出异常病理反应。