Potential therapeutic targets and repurposed drug identified for endometriosis

Researchers from the Chinese University of Hong Kong (CUHK) have identified two novel potential therapeutic targets and a drug approved for dry eyes that can be repurposed for treatment of endometriosis.

Using an artificial intelligence (AI)–driven target discovery platform, the researchers performed a meta-analysis of endometriosis-associated datasets based on ectopic endometrium tissues to identify potential therapeutic targets. This, together with expression and pathway analysis, revealed guanylate-binding protein 2 (GBP2) and haematopoietic cell kinase (HCK) as novel potential targets previously unreported in endometriosis studies, and integrin beta 2 (ITGB2) as a potential therapeutic target for drug repurposing. [Adv Sci (Weinh) 2024;doi:10.1002/advs.202406565]

Lifitegrast, an ITGB2 antagonist approved for treatment of dry eyes, was found to effectively suppress endometriotic growth when administered subcutaneously or intraperitoneally in preclinical murine endometriosis models.

“Notably, these discoveries were made within 1 year, highlighting the extraordinary speed of AI-aided drug and target discovery,” the researchers noted.

“GBP2 is implicated in regulation of immune and inflammatory processes, while HCK is involved in cell proliferation and survival signalling. In our study, GBP2 and HCK expression was found to be elevated in stromal and epithelial cells in human ovarian and peritoneal endometriotic tissue samples compared with controls,” explained Professor Ronald Wang of the Department of Obstetrics and Gynaecology, CUHK, who led the study.

“siRNA-mediated knockdown of GBP2 and HCK significantly reduced cell viability and proliferation while stimulating apoptosis in endometrial stromal cells,” the authors wrote. “In subcutaneous and intraperitoneal endometriosis mouse models, siRNAs targeting GBP2 and HCK notably reduced lesion volume and weight, with decreased proliferation and increased apoptosis within lesions.”

Similarly, ITGB2 expression was found to be significantly elevated in stromal and epithelial cells within human ovarian and peritoneal endometriotic tissue samples compared with controls.

ITGB2 inhibition with lifitegrast, either subcutaneously or intraperitoneally, demonstrated therapeutic efficacy in treating endometriosis in mouse models. Subcutaneous administration of lifitegrast at 0.25 or 0.50 mg/kg led to significant reductions in volume and weight of endometriotic lesions, while dosages of 0.50 and 0.75 mg/kg significantly suppressed endometriotic cell proliferation and increased apoptotic cell number in lesions compared with control tissue. Intraperitoneal lifitegrast at 0.25 or 0.75 mg/kg significantly reduced ectopic lesion growth, while 0.75 mg/kg suppressed endometriotic cell proliferation and increased apoptosis.

“These findings indicate that lifitegrast may be a viable treatment option for endometriosis in clinical settings, which is to be confirmed in a clinical trial,” suggested Wang.

“Hormone therapy is currently used in first-line treatment of endometriosis. However, the relief is often only temporary, with a high risk of recurrence and concerns about long-term side effects,” said Dr Jacqueline Chung of the Department of Obstetrics and Gynaecology, CUHK.

“The new potential therapeutic targets identified in our study can hopefully be developed into precise treatment options and improve patients’ quality of life,” said Professor Liona Poon, Chairperson of the Department of Obstetrics and Gynaecology, CUHK.