(SST) Southeastern Brain Tumor Foundation (SBTF) Award (2023 Award Winner): EZH2 Inhibition as a Potential Therapeutic Avenue in the Treatment of Meningioma

Introduction: High grade meningiomas provide challenges to treatment as these neoplasms are more likely to recur and are associated with decreased long-term survival. Recent works demonstrate the epigenetic modifier, EZH2, to be increased in higher grade meningiomas, and to correlate with poor survival. Selective targeting of EZH2 has shown promise in other malignancies with overexpression of or gain-of-function mutations in EZH2, leading to encouraging findings. In addition, combination of EZH2 inhibition and radiation therapy appeared beneficial in rhabdoid tumors and other malignancies. We sought to investigate the effect of EZH2 inhibition on meningioma cell growth and viability, using a panel of in vitro models.

Methods: Four human immortalized meningioma cell lines (IOMM-Lee, CH157, SF1335, and BenMen1), three mouse meningioma cell lines (MGS1, MGS2, and MGS3), and a panel of human primary cell cultures (WHO grade I and grade II) with varying protein expression of NF2, SMARCB1, and EZH2, were selected for investigation. Cells were treated with a selective small molecule inhibitor of EZH2. Cell proliferation was assessed via cell counting and clonogenic assay. Response to radiation treatment alone or in combination with EZH2 inhibition was assessed via proliferation assay.

Results: EZH2 inhibition significantly impairs meningioma cell proliferation, at varying IC50s, in all cell lines and primary cultures tested. EZH2 inhibition resulted in significantly decreased colony formation in a high-grade cell line. Furthermore, addition of EZH2 inhibition to radiation treatment resulted in a further significant decrease in cell proliferation in a subset of cell lines and primary meningioma cell cultures.

Conclusion : Our work demonstrates that EZH2 inhibition results in growth inhibition across all meningioma cell lines and cell cultures tested, while addition of EZH2 inhibition to radiation demonstrates further inhibition of cell proliferation in a subset of cell lines and cell cultures. This work provides the framework for further investigation of EZH2 inhibition in meningioma.