REPURPOSING OF THE ANTI-VIRAL DRUG RIBAVIRIN AS A POTENTIAL MENINGIOMA THERAPEUTIC

Abstract INTRODUCTION High grade meningiomas provide significant challenges to treatment. Recent works have demonstrated meningiomas to express higher levels of the epigenetic regulator enhancer of zeste homolog 2 (EZH2), as well as the protein eIF4E, a key player in translation. These two molecules are demonstrated targets of the well tolerated antiviral drug, ribavirin, which has recently shown promise as an anti-neoplastic agent. Based on these findings we sought to investigate the effect of ribavirin on meningioma tumorigenesis utilizing in vitro and in vivo meningioma models. METHODS Several immortalized human meningioma cell lines, three immortalized mouse meningioma cell lines, and a panel of human primary cell cultures were assessed. Cell proliferation, cell colony formation, clonogenic assay, and cell death were assessed. Furthermore, we tested ribavirin efficacy in vivo utilizing two aggressive high grade syngeneic orthotopic allograft meningioma models in FVB WT mice. RESULTS We provide evidence that ribavirin significantly impairs meningioma cell growth and proliferation, and induces cell death in vitro. Most importantly, we demonstrate that ribavirin alone significantly improves the survival of mice orthotopically implanted with MGS2 cells. Ribavirin-treated animals exhibited a significantly increased median survival (67 days) compared to controls (41 days; p=0.0009;) in an orthotopic convexity meningioma xenograft model. Furthermore, ribavirin treatment resulted in increased survival in an orthotopic skull base meningioma xenograft model. CONCLUSION Our work establishes that ribavirin is effective against meningioma in vitro and in vivo. Ribavirin treatment reduced proliferation in all cell lines tested, in both high and low grade models, induced cell death, and prolonged survival in two aggressive in vivo models, potentially via modulation of the EZH2 and eIF4E pathways. Given the lack of medical therapy for high grade meningiomas, these findings provide a framework for further investigation into ribavirin’s effects on meningioma tumorigenesis, and demonstrate ribavirin as a potential new therapeutic option in the treatment of meningioma.