Repurposing CRH antagonists for the treatment of endometriosis

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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.