DDRE-39. REPURPOSING CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS WITH GUIDANCE BY METHYLATION PROFILES

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2021-11, Vol.23 (Supplement_6), p.vi82-vi83
• Main Authors: Tran, Anh, Wang, Wenxia, Scholtens, Denise, Zhang, Lyndsee, Pokorny, Jenny, Wang, Yufen, Baran, Aneta, Sahm, Felix, Aldape, Kenneth, James, David, Horbinski, Craig
• Format: Article
• Language: English
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noab196.323

Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas are categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy, 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 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 or longer PFS at FDR-adjusted p < 0.05. Using Cytoscape/Reactome FI software, 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 seventeen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. As monotherapy, the effects of docetaxel on meningioma were attenuated by multidrug resistance protein 1 (ABCB1) and Cytochrome P450 1B1 (CYP1B1). Docetaxel at 2µM augment double-stranded DNA damage caused by irradiation in vitro, leading to increased cell death. In animal model, low doses of docetaxel and radiation therapy had synergistic effects, increasing survival of mice intracranially implanted with human meningioma 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.