A Novel Target for the Treatment of Endometriosis

描述（由申请人提供）：子宫内膜异位症是育龄妇女严重盆腔疼痛、经期疼痛、性交困难和不孕的主要原因，在美国的诊断和治疗费用估计为220亿美元。该疾病通常在绝经后消退，高度依赖雌激素。腹腔镜手术可以暂时缓解疼痛，但保守估计5年后复发率为50%。药物治疗的益处也是有限的。例如，通过6个月的促性腺激素释放激素（GnRH）激动剂治疗来抑制卵巢雌激素的产生，有明显的骨质流失风险，并不比口服避孕药治疗更有效，而且在5年内症状复发率也有50%或更高。子宫内膜异位症病变内源性合成雌激素，这可能具有病理意义。阻断雌激素合成最后一步的芳香化酶抑制剂在绝经后子宫内膜异位症的罕见病例中有效的报道支持了这一结论。但芳香化酶抑制剂不用于治疗绝经前妇女的子宫内膜异位症，因为它们会刺激卵巢囊肿的形成。显然，迫切需要新的治疗子宫内膜异位症的药物。我们已经确定了一种孤儿核受体的小分子拮抗剂，该受体控制涉及从胆固醇重新合成类固醇激素的主要基因。与正常子宫内膜相比，异位子宫内膜植入物中该受体的表达高度升高，并且该孤儿受体的过度表达与局部雌激素生物合成的驱动因素密切相关。受体过表达可能调节子宫内膜异位症病理的其他方面，除了雌激素的产生，口服生物可利用受体拮抗剂代表了直接靶向子宫内膜异位症病变的新治疗方法。本提案的目的是：(i)证明专有受体拮抗剂抑制体外培养的子宫内膜异位症基质细胞中的类固醇基因表达和雌激素合成；同时，我们将测量人类肾上腺原代培养物中的类固醇合成，其中受体也得到表达，以评估受体拮抗剂的组织特异性；（ii）评估治疗效果的另一个终点，受体拮抗剂在培养中抑制子宫内膜异位症细胞生长和凋亡；（iii）合成效价更高（EC50 < 10 nM）的拮抗剂配体，用于靶细胞检测。同一受体存在于垂体促性腺激素和卵巢中，因此拮抗剂也可能抑制促性腺激素的分泌和卵巢雌激素的合成。我们的长期目标是确定口服生物可利用的候选药物，确定对体内正常类固醇形成的影响，并与一家大型制药公司合作进行进一步的临床前和临床开发。

DESCRIPTION (provided by applicant): Endometriosis is a major cause of severe pelvic pain, pain during menstruation, dyspareunia and infertility in women of child-bearing age with an estimated $22 billion cost of diagnosis and treatment in the U.S. The disease ordinarily regresses after menopause and is highly dependent on estrogen. Laparoscopic surgery provides temporary pain relief, but the recurrence rate is conservatively estimated to be 50% after five years. The benefits of drug treatment are also limited. For example, suppression of ovarian estrogen production by six months of gonadotropin-releasing hormone (GnRH) agonist therapy carries a significant risk of bone loss, is not obviously more effective than treatment with oral contraceptives, and also has a 50% or higher recurrence of symptoms within 5 years. Endometriotic lesions synthesize estrogen endogenously and this may be pathologically significant. Reports that aromatase inhibitors, which block the final step of estrogen synthesis, are effective in rare cases of post-menopausal endometriosis support this conclusion. But aromatase inhibitors are not used for treatment of endometriosis in pre-menopausal women because they stimulate ovarian cyst formation. Clearly, new medical therapies for endometriosis are desperately needed. We have identified small molecule antagonists to an orphan nuclear receptor that controls the major genes involved in de novo steroid hormone synthesis from cholesterol. Expression of this receptor is highly elevated in ectopic endometrial implants when compared to normal endometrium, and overexpression of this orphan receptor is strongly implicated as a driver of local estrogen biosynthesis. Receptor overexpression may regulate other aspects of endometriotic pathology, in addition to estrogen production, and orally bioavailable receptor antagonists represent a new therapeutic approach to directly target the endometriotic lesion. The objectives of this proposal are: (i) to demonstrate that proprietary receptor antagonists inhibit steroidogenic gene expression and estrogen synthesis in cultured endometriotic stromal cells; in parallel, we will measure steroid synthesis in human primary adrenal cultures, where the receptor is also expressed, to assess tissue specificity of receptor antagonists; (ii) to evaluate an alternative endpoint of therapeutic efficacy, receptor antagonist suppression of endometriotic cell growth and apoptosis in culture; and (iii) to synthesize antagonist ligands with improved potency (EC50 < 10 nM) for the target cell assays. The same receptor is present in pituitary gonadotropes and the ovary and thus antagonists may also suppress gonadotropin hormone secretion and ovarian estrogen synthesis. Our long-term objective is to identify orally bioavailable drug candidates, to characterize effects on normal steroidogenesis in vivo, and to partner with a major pharmaceutical company for further preclinical and clinical development. PUBLIC HEALTH RELEVANCE: Endometriosis affects 6-10% of women of child-bearing age, and it is a leading cause of disability and pelvic pain in this age group. Of women treated for infertility, about 30% have endometriosis. In 1991-2, for example, 2.2% of hospital admissions in the U.S. were related to endometriosis with an average stay of 3.5 days. There is a major unmet need for new pharmacological treatments that can palliate the disease and delay recurrence after surgery. The proposed research will generate proof-of-principle data on antagonists to a previously unexplored drug target that is highly expressed in endometriosis and appears to be central to the pathophysiology of this debilitating disease.