EXTH-65. USING METHYLATION PROFILES TO GUIDE THE REPURPOSING OF CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS

Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas grow slowly, hence categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy for meningioma, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and identified associations of methylation at individual CpG sites as detected by the Illumina 450k platform with PFS. Subsequently, we searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter PFS (positive hazard ratios (HRs)) and with longer PFS (negative HRs) at FDR-adjusted p < 0.05. Using Cytoscape/Reactome FI app, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the sixteen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.