Authors: Bradley King; Briana Prager; Harish Vasudevan, MD, PhD; Derrick Lee; David Raleigh, MD, PhD; Jeremy Rich, MD (La Jolla, CA)

Introduction: Treatment of meningiomas, the most common primary brain tumor, is confounded by genetic heterogeneity and difficulty in targeting known tumorigenic drivers. At present, no effective medical therapies exist for atypical or malignant meningiomas. The present work better characterizes the super-enhancer landscape in high-grade and recurrent meningiomas to identify critical regulators of cellular function and unmask new therapeutic targets. Methods: H3K27Ac ChIP-seq was performed on 33 primary meningioma samples and three early-passage arachnoid granulation cell lines to identify enhancers. Tumor-specific super-enhancers were identified by subtracting super-enhancers present in normal tissue. In vitro studies utilizing CRISPR knockouts or pharmacologic inhibition of pathways of interest were performed to determine whether identified targets influence meningioma cell viability. Results: Analysis of the enhancer landscape identified 1490 super-enhancers, 1104 of which were tumor-specific, and clustering revealed grade-specific subgroups. Disrupting selected pathways impaired cell survival across a panel of five meningioma cell lines to a significantly greater degree than in arachnoid granulation cells. Small-molecule inhibition of the most sensitive gene product yielded a 10-fold more potent response in meningioma, resulting in 90% cell death at 1 µM concentration. Conclusion: Characterization of the enhancer landscape revealed novel therapeutic targets in meningioma. Our in vitro results warrant further investigation to assess the efficacy of targeted treatment on inhibiting tumor growth and progression in animal models.