Recently, germline loss-of-function mutations in SMARCE1, which encodes the BAF57 subunit of the mammalian Switch/Sucrose Non-Fermentable (mSWI/SNF) ATP-dependent chromatin remodeling complex, were identified in 100% of clear cell meningioma (CCM) patients. CCM is rare histological grade II neoplasm of the central nervous system (CNS) that disproportionally affects children and adolescents. Although surgical resection and radiation effectively treat most meningiomas, CCM exhibits uniquely aggressive clinical behavior, with a high rate of recurrence and extra-CNS metastasis. mSWI/SNF chromatin remodeling complexes are key transcriptional machines, ubiquitously expressed in every human cell type. mSWI/SNF complexes are fueled by ATP hydrolysis to orchestrate a diverse set of alterations to chromatin architecture (i.e. ejection, destabilization, or restructuring of nucleosomes), which grant transcription factors access to tightly packaged nucleosomal DNA, resulting in context-specific regulation of gene expression. Subunits of the mSWI/SNF complex are mutated in over 20% of cancers across a wide range of tissue types and often represent the most frequently mutated gene in these cancers. For instance, ARID1A and SMARCB1, each encoding subunits of the mSWI/SNF complex, are respectively mutated in >60% of ovarian clear cell tumors and >98% of childhood malignant rhabdoid tumors. Interestingly, genetic perturbations in mSWI/SNF have been shown to exhibit key synthetic lethal relationships with targets of established epigenetic drugs, prompting a surge of drug discovery efforts for mSWI/SNF-driven cancers. Owing to the lack of understanding regarding the mechanistic underpinnings of CCM, targeted therapeutics predicted to exhibit efficacy in this disease have yet been identified. SMARCE1 mutations appear to cause CCM via a classical tumor suppressor mechanism whereby patients bear familial germline loss of one allele, concomitant with either loss or mutation of the second allele, culminating in complete loss of SMARCE1 protein. The current study aims to identify therapeutic vulnerabilities in CCM by (1) probing the effect of SMARCE1 loss on the biochemical architecture of the multimeric mSWI/SNF (BAF) complex; (2) defining the functional consequences of SMARCE1 loss in promoting aberrant BAF complex targeting genome-wide and oncogenic gene expression patterns, to identify downstream pathways that may be amenable to therapeutic intervention; and (3) screening a small library of FDA-approved small molecules for activity in cell line models of SMARCE1-deficient clear cell meningioma. Successful completion of the work outlined in this NIH F31 proposal will advance our understanding of the pathogenesis of mSWI/SNF-deficient neoplasms and identify novel therapeutic approaches toward targeting these tumors.