EXTH-88. DOCETAXEL TARGETS AGGRESSIVE METHYLATION PROFILES AND SERVES AS A RADIOSENSITIZER IN HIGH-RISK MENINGIOMAS

Abstract

Abstract DNA methylation profiling has emerged as a transformative prognostic tool in meningiomas, identifying distinct epigenetic subgroups that share unique clinical and biological features. Hypothesizing that methylation patterns may also reflect underlying pathogenic mechanisms, we investigated if this modality could be informative for the selection of efficacious chemotherapies in meningiomas, focusing on FDA-approved compounds that are well-tolerated in patients. Using a methylation dataset of 210 tumors, we identified 981 genes in which adjacent CpG sites were predictive of progression-free survival. Pathway enrichment of these genes nominated Docetaxel as a candidate therapeutic; a well-established taxane that is routinely used for breast, prostate, and lung cancers. Using 15 primary patient-derived cultures and 2 cell lines, we found that Docetaxel could inhibit meningioma growth at concentrations that were favorable relative to other cancers. This drug triggered apoptosis in meningiomas of all tumor grades and methylation classes, with IC50 values ranging from 0.8nm to 4.4nm in vitro. Combining Docetaxel with radiation therapy resulted in synergistic cytotoxic effects on meningioma cultures, associated with elevated markers of cell death and dsDNA breaks. We confirmed our results via orthotopic meningioma mouse models of the cell lines CH157 and IOMM-Lee, which exhibited dose-dependent improvements in mortality and tumor volume in response to Docetaxel and radiation. Our results leverage DNA methylation patterns to repurpose FDA-approved medications in the treatment of meningiomas, and suggest a clinical trial of Docetaxel with radiotherapy may be efficacious in higher-grade lesions.