Applying a computational transcriptomics-based drug repositioning pipeline to identify therapeutic candidates for endometriosis

Abstract

Endometriosis is a common, inflammatory pain disorder comprised of disease in the pelvis and abnormal uterine lining and ovarian function that affects ~200 million women of reproductive age worldwide and up to 50% of those with pelvic pain and/or infertility. Existing medical treatments for endometriosis-related pain are often ineffective, with individuals experiencing minimal or transient pain relief or intolerable side effects limiting long-term use - thus underscoring the pressing need for new drug treatment strategies. In this study, we applied a computational drug repurposing pipeline to endometrial gene expression data in the setting of endometriosis and controls in an unstratified manner as well as stratified by disease stage and menstrual cycle phase in order to identify potential therapeutics from existing drugs, based on expression reversal. Out of the 3,131 unique genes differentially expressed by at least one of six endometriosis signatures, only 308, or 9.8%, were in common. Similarities were more pronounced when looking at therapeutic predictions: 221 out of 299 drugs identified across the six signatures, or 73.9%, were shared, and the majority of predicted compounds were concordant across disease stage-stratified and cycle phase-stratified signatures. Our pipeline returned many known treatments as well as novel candidates. We selected the NSAID fenoprofen, the top therapeutic candidate for the unstratified signature and among the top-ranked drugs for the stratified signatures, for further investigation. Our drug target network analysis shows that fenoprofen targets PPARG and PPARA which affect the growth of endometrial tissue, as well as PTGS2 (i.e., COX2), an enzyme induced by inflammation with significantly increased gene expression demonstrated in patients with endometriosis who experience severe dysmenorrhea. NSAIDs are widely prescribed for endometriosis-related dysmenorrhea and nonmenstrual pelvic pain. Our analysis of clinical records across University of California healthcare systems revealed that while NSAIDs have been commonly prescribed to the 61,306 patients identified with diagnoses of endometriosis, dysmenorrhea, or chronic pelvic pain (36,543, 59.61%), fenoprofen was infrequently prescribed to those with these conditions (5, 0.008%). We tested the effect of fenoprofen in an established rat model of endometriosis and determined that it successfully alleviated endometriosis-associated vaginal hyperalgesia, a surrogate marker for endometriosis-related pain. These findings validate fenoprofen as a potential endometriosis therapeutic and suggest the utility of future investigation into additional drug targets identified.

Endometriosis in the era of precision medicine and impact on sexual and reproductive health across the lifespan and in diverse populations

“…The development and availability of large‐scale genomic, transcriptomic, and other molecular profiling technologies in publicly available databases, in combination with the deployment of the network concept of drug targets and the power of phenotypic screening, provide an unprecedented opportunity to advance rational drug repositioning and data‐driven development of drug combinations based on the ability of single or multiple therapeutic agents to perturb entire molecular networks away from disease states in cell‐based and animal models. We and others have used aforementioned approaches to identify new uses for existing drugs for a number of different indications including inflammatory bowel disease, 164,165 cancer, 166 Alzheimer's disease, 167 COVID19, 168 and most recently endometriosis 160 . Genomic and transcriptomic technologies allow us to extract large amounts of data from patient samples, elucidating previously unknown factors involved in disease, which could lead to identifying new therapeutic strategies.…”

“…Selective progesterone receptor modulators (SPRMs) have been used but have hepatotoxicity that limits continuous therapy, and selective estrogen receptor modulators (SERMs) have found applications in select cases coupled with GnRH agonists for severe and medially recalcitrant endometriosis‐related pain 159 . Novel approaches are being pursued, including mining transcriptomic data and using a drug repositioning pipeline (see below) 160 …”

“…We and others have used aforementioned approaches to identify new uses for existing drugs for a number of different indications including inflammatory bowel disease, 164,165 cancer, 166 Alzheimer's disease, 167 COVID19, 168 and most recently endometriosis. 160 Genomic and transcriptomic technologies allow us to extract large amounts of data from patient samples, elucidating previously unknown factors involved in disease, which could lead to identifying new therapeutic strategies. As we learn more about the complex mechanisms associated with endometriosis and its related comorbid conditions, it is increasingly clear that treatments will likely require both precision medicine and combination therapeutic approaches.…”

“…159 Novel approaches are being pursued, including mining transcriptomic data and using a drug repositioning pipeline (see below). 160 Kinase signaling pathways have been targets for endometriosis-related pain, including, IKkb/NFkB, MAPK (ERK1/2, p38, JNK), and PI3K/AKT/ mTOR, 161 although the current generation of kinase inhibitors carry potential for significant adverse side effects. Several immunomodulatory agents have also been evaluated for endometriosisrelated pain, infertility, and lesion size in either completed or ongoing clinical trials in patient and in animal models.…”