EXTH-146. The Pharmacological Atlas of Meningiomas

Abstract There are currently no systemic treatment options available for patients with recurrent or refractory meningiomas. This study aims to address this gap by developing a comprehensive pharmacological atlas of FDA-approved oncology drugs using a large cohort of patient-derived meningioma organoids. We constructed a pharmacological atlas of meningiomas by generating 8,950 dose-response curves from 179 FDA-approved oncology drugs tested on over 60,000 tumor organoids derived from 50 meningioma patients. The cohort included 37 grade 1, 11 grade 2, and 2 grade 3 meningiomas, with 11 of these being recurrent tumors. Of the drugs tested, 21% (n=39/179) demonstrated sensitivity (median IC50 < 30 µM), with significant enrichment for topoisomerase, RNA/protein synthesis, proteasome, and HDAC inhibitors. The top five drugs with the lowest IC50 values were romidepsin, dactinomycin, carfilzomib, plicamycin, and omacetaxine, with median values of 10, 31, 145, 303, and 400 nM, respectively. Hierarchical clustering of IC50 data revealed four distinct drug response clusters characterized by sensitivity to tyrosine kinase inhibitors, sensitivity to classical chemotherapeutics, overall resistance, and heterogeneous drug sensitivity. Additionally, an ongoing multiomics analysis, including RNA and DNA-panel sequencing and methylation profiling, is being conducted to correlate genetic alterations with drug responses and drug clusters. Considering the ratio of peak serum concentration (Cmax) to IC50 as a potential predictor of treatment efficacy (>1), the HDAC inhibitors belinostat (74.5), romidepsin (69.7), along with the proteasome inhibitor carfilzomib (34.6), and the anthracyclines epirubicin (2.6), and doxorubicin (1.8), and the PI3K inhibitor idelalisib (1.6) are the most promising drug candidates for further evaluation. This study offers the first comprehensive insight into the pharmacological landscape of meningiomas, providing a crucial foundation for future clinical trials aimed at developing systemic treatments for aggressive meningiomas.