Repurposing CRH antagonists for the treatment of endometriosis

项目摘要 子宫内膜异位症是一种慢性疾病，影响全球10%的育龄妇女。不幸的是， 59%的子宫内膜异位症患者对现有的治疗没有反应，并继续遭受 治疗停止后，椎间盘突出相关疼痛或复发性疼痛。因此， 目前的治疗重点是迫切需要的。促肾上腺皮质激素释放激素受体 1型（CRHR 1）是一个很大程度上未开发的靶点。促肾上腺皮质激素释放激素（CRH），可激活 CRHR 1是下丘脑-垂体-肾上腺（HPA）轴中整合应激和 大脑和周围组织的内分泌反应。CRHR 1在子宫内膜中丰富， 卵巢，并在发育卵巢组织中发挥作用，正如该团队以前的工作所证明的那样。 CRHR 1拮抗剂被引入情绪和胃肠道疾病的临床试验， 对这些疾病的影响，从未获得商业用途的批准。以前的研究工作 研究小组证明，在临床前研究中经常使用的CRHR 1拮抗剂antalarmin的短期治疗 实验，显示子宫内膜异位症的发展减少了30%，体重减少了60%， 子宫内膜异位囊肿的大小。在继续这些努力的过程中，总体目标是发展和 将CRHR 1拮抗剂商业化以治疗子宫内膜异位症。研究小组最近将重点研究一种化合物 专利，并达到2期临床试验，但对抑郁症，焦虑症或酗酒无效。到 开始解决我们的目标，两个具体目标的设计：在目标1，我们将确定的有效性， 用于子宫内膜异位症治疗的临床相关CRHR 1拮抗剂，包括其降低 相关的疼痛。目的2将确定CRHR 1拮抗剂是否影响性腺轴的周期性激素分泌， 活性，独立于抗增殖活性。这两个目标都将使用完善的 子宫内膜异位症的自体移植大鼠模型，允许有效的定量和表征 囊泡。完成的目标将揭示阻止子宫内膜异位症进展的最佳干预措施 并预测与CRHR 1在性腺系统中的作用直接相关的可能作用机制。 未来的工作将集中在CRHR 1拮抗作用如何影响生育力和繁殖力，这是关键因素 申请重新进入FDA的临床试验CRHR 1拮抗剂进入商业领域 具有减少子宫内膜异位症妇女手术干预的强大潜力， 节省了数千美元的医疗保健和间接成本。研究小组已经确定了 重新使用CRHR 1拮抗剂，但在重新引入临床试验之前，需要额外的作用证据， 需要临床前的有效性。

PROJECT SUMMARY Endometriosis is a chronic condition that affects 10% of reproductive-aged women worldwide. Unfortunately, up to 59% of women with endometriosis do not respond to the available treatments and continue to suffer from endometriosis-associated pain or recurrent pain after treatment cessation. Therefore, treatment alternatives that deviate from the current therapeutic focus are urgently needed. The corticotrophin-releasing hormone receptor type 1 (CRHR1) is a largely unexplored target. Corticotropin-releasing hormone (CRH), which activates the CRHR1, is a critical molecule in the hypothalamic-pituitary-adrenal (HPA) axis that integrates stress and endocrine responses both in the brain and in peripheral tissues. CRHR1 is abundant in the endometrium and ovaries and has a role in developing endometriotic tissues, as demonstrated by the team's previous work. CRHR1 antagonists were introduced into clinical trials for mood and gastrointestinal disorders with little to no effect on those diseases and have never reached approval for commercial use. Previous work from the research team demonstrated that short-term treatment with antalarmin, a CRHR1 antagonist frequently used in pre-clinical experimentation, showed a 30% decrease in endometriosis development and a 60% decrease in the weight and size of endometriosis vesicles. In continuation of these efforts, the overarching goal is to develop and commercialize CRHR1 antagonists to treat endometriosis. The research team will focus on a compound recently out of patent and reached Phase 2 clinical trials but was not effective for depression, anxiety, or alcoholism. To begin addressing our goal, two specific aims were designed: on Aim 1, we will determine the effectiveness of a clinically relevant CRHR1 antagonist for endometriosis treatment, including its effectiveness in decreasing associated pain. Aim 2 will determine whether the CRHR1 antagonist affects the gonadal axis's cyclic hormonal activity, independent of antiproliferative activity. Both aims will be done using the well-established autotransplantation rat model of endometriosis, allowing for effective quantification and characterization of endometriotic vesicles. Completed aims will reveal the optimal intervention for halting endometriosis progression and predict possible mechanisms of action directly associated with the role of CRHR1 in the gonadal system. Future efforts will focus on how the CRHR1 antagonism impacts fertility and fecundity, which are critical factors to apply for re-introduction into clinical testing at the FDA. Bringing CRHR1 antagonists into the commercial field have the strong potential of decreasing surgical interventions in women with endometriosis, resulting in thousands of dollars saved in healthcare and indirect costs. The research team has identified the potential to repurpose CRHR1 antagonists, but before being re-introduced into clinical trials, additional proof of action and pre-clinical effectiveness is needed.