STING inhibition as a therapeutic target for endometriosis

Project Summary/Abstract Endometriosis affects about 10% of all reproductive-age women and it is one of the main causes of pelvic pain and infertility. Current FDA-approved hormonal therapies are often limited in efficacy, counterproductive to fertility and with side effects affecting endogenous hormone steroid levels, resulting in cessation of the reproductive cycle, hirsutism, postmenopausal symptoms, and osteoporosis. Alternative therapeutic strategies are geared towards drugs without hormonal side effects but with limited therapeutic efficacy, including NSAID treatment for pain. To date, no effective therapies without hormonal side effects exist. Thus, studies aimed at identifying novel therapeutic targets against endometrial inflammation and fibrosis devoid of unwanted side effects stemming from estrogen deficiency, is a major clinical need. Recent evidence indicates that stimulator of interferon genes (STING) is upregulated in endometriosis lesions and recent data from our team and others show that type I and II (IFN) are associated with more advanced stages of endometriosis, independently of the menstrual cycle and hormonal status, with STING-dependent IFN related genes emerging as novel stromal markers of endometriosis. Nitro-fatty acids (NO2-FAs) have emerged as potent anti-inflammatory and anti- fibrotic agents in numerous experimental models of inflammation, metabolism and fibrosis, and successfully completed phase I and II clinical trials. Our collaborators identified residues Cys88 and Cys91 of STING as NO2-FA targets. In addition to the first generation NO2-FAs, we identified NO2-FA-derived New Chemical Entities (NCEs), compatible with oral delivery and showing high efficacy on STING inhibition and negligible toxicity in vivo. Considering the unique pathogenesis of endometriosis, involving endometrial inflammation and fibrosis along with the well-established anti-inflammatory and anti-fibrotic properties of NO2-FA, we show that: 1) oral delivery of a first generation NO2-FA, NO2-conjugated linoleic acid, protects against endometriosis in a syngeneic model in vivo; 2) Loss-of-STING function protects against experimental endometriosis; 3) A novel NCE, CP-36, with improved STING affinity (IC50) and low toxicity in vivo is readily bioavailable as an oral therapy against endometriosis. Based on these premises, the project will test the central hypothesis that novel orally bioavailable STING inhibitors protect against endometriosis and associated pain by inhibiting inflammation and fibrosis. Using our unique mouse model, STING C88A/C91A knock-in, click chemistry, and well-established models of peritoneal endometriosis, including a regression study, we will define the therapeutic specificity of CP-36 as bona fide STING inhibitor in endometriosis (aim 1) and establish that STING inhibition by oral delivery of CP-36 reduces endometriosis (aim 2). This study will provide functional and mechanistic evidence for novel NO2-FA-based STING inhibitors as potential non-hormonal therapeutic drugs for endometriosis, thus paving the way for the accelerated development of novel therapeutic strategies and a paradigm change in clinical treatment and management of this disease.