A Novel Target for the Treatment of Endometriosis

治疗子宫内膜异位症的新靶点

• 批准号: 8202685
• 负责人: PAUL D CROWE
• 金额: $ 22.08万
• 依托单位: ORPHAGEN PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2013-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202685
• 关键词: Abbreviations; Admission activity; Adrenal Glands; Affect; Agonist; Anabolism; Apoptosis; Aromatase; Aromatase Inhibitors; Back; Bioavailable; Biological Assay; Biopsy; Bone Density; Cell Culture Techniques; Cell Proliferation; Cells; Cholesterol; Clinical; Data; Development; Diagnosis; Differentiation and Growth; Disease; Drug Delivery Systems; Drug Kinetics; Dyspareunia; Endometrial; Endometrium; Enzyme Gene; Estrogens; Family; Female of child bearing age; Functional disorder; Gene Expression; Genes; Goals; Gold; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Growth; Hormones; Hospitals; Human; Hypothalamic structure; Implant; Infertility; Laparoscopic Surgical Procedures; Lead; Lesion; Ligands; Lipids; Measures; Medical; Menopause; Menstruation; Modality; Nuclear; Nuclear Orphan Receptor; Nuclear Receptors; Operative Surgical Procedures; Oral Contraceptives; Orphan; Ovarian; Ovarian Ablation; Ovarian Cysts; Ovary; Pain; Papio; Pathogenesis; Pathology; Patients; Pelvic Pain; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phase; Pituitary Gland; Positioning Attribute; Postmenopause; Premenopause; Production; Property; Publishing; Recurrence; Reporting; Research; Retinoid Receptor; Risk; Rodent; Role; SF1; Safety; Series; Specificity; Steroid biosynthesis; Steroids; Stromal Cells; Symptoms; Testing; Therapeutic; Thyroid Gland; Tissue Differentiation; Tissues; Treatment Efficacy; Validation; Woman; activating transcription factor; age group; base; bone loss; cell growth; cost; disability; drug candidate; drug discovery; effective therapy; endometriosis; improved; in vivo; innovation; member; nonhuman primate; novel; novel therapeutic intervention; overexpression; pre-clinical; receptor; receptor expression; reproductive axis; small molecule; steroid hormone; transcription factor

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.

描述（由申请人提供）：子宫内膜异位症是严重的骨盆疼痛，月经期间疼痛，性交困难和育龄女性不孕症的主要原因，据估计，在美国，诊断和治疗费用估计为220亿美元，疾病在更绝期后的疾病通常会消失，并且非常依赖雌激素。腹腔镜手术可暂时缓解疼痛，但五年后的复发率估计为50％。药物治疗的好处也受到限制。例如，促促性腺激素释放激素（GNRH）激动剂疗法抑制卵巢雌激素产生的产生具有显着的骨质损失风险，显然并不比口服避孕药的治疗更有效，并且在5年内还具有50％或更高的症状复发。子宫内膜损伤内源性地合成雌激素，这可能具有病理意义。报道说，阻断雌激素合成的最后一步的芳香酶抑制剂在极少数绝经后子宫内膜异位症的情况下是有效的，这支持了这一结论。但是，芳香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，迫切需要新的子宫内膜异位症医疗疗法。我们已经将小分子拮抗剂确定为孤儿核受体，该孤儿核受体控制着从胆固醇的从头类固醇激素合成的主要基因。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表达很大程度上暗示是局部雌激素生物合成的驱动因素。受体过表达除了产生雌激素外，还可以调节子宫内膜病理学的其他方面，口服可生物可用的受体拮抗剂代表了一种直接靶向子宫内膜损伤的新方法。该提案的目标是：（i）证明专有受体拮抗剂抑制培养的子宫内膜含量基质细胞中的类固醇基因表达和雌激素合成；同时，我们将测量人类原发性肾上腺培养物中的类固醇合成，并在其中表达受体，以评估受体拮抗剂的组织特异性。 （ii）评估治疗功效的替代终点，受体拮抗剂抑制子宫内膜细胞生长和培养中凋亡； （iii）以提高靶细胞测定的效力（EC50 <10 nm），合成拮抗剂配体。垂体性促性腺体和卵巢中存在相同的受体，因此拮抗剂也可能抑制促性腺激素激素分泌和卵巢雌激素合成。我们的长期目标是确定口服可生物利用的候选药物，以表征对体内正常类固醇生成的影响，并与一家大型制药公司合作，以进一步临床前和临床开发。 公共卫生相关性：子宫内膜异位症影响6-10％的育龄妇女，这是该年龄段的残疾和骨盆疼痛的主要原因。在接受不育治疗的妇女中，约有30％患有子宫内膜异位症。例如，在1991 - 2年，美国有2.2％的住院与子宫内膜异位症有关，平均停留时间为3.5天。对新的药理治疗的主要需求可以使疾病抑制并延迟手术后复发。拟议的研究将对拮抗剂产生原则数据，以对以前未经探索的药物靶靶标产生高度表达的子宫内膜异位症，并且似乎是这种令人衰弱的疾病的病理生理学的核心。