Project summary The meningeal lining of the central nervous system is critical for neuronal development and homeostasis. However, meningeal tumors account for the majority of primary intracranial cancers. Meningiomas are overwhelmingly diagnosed in older adults, women, and African American patients, all of which are underrepresented in clinical trials. Thus, there are no effective pharmacologic treatments for meningioma patients. New therapies have been further encumbered by limited understanding of meningioma biology and a lack of tractable models for preclinical meningioma investigation. To address these problems, we performed multiplatform molecular profiling on 565 human meningiomas from patients with comprehensive follow-up data to discover that meningioma is comprised of 3 epigenetic subgroups with distinct clinical outcomes. Moreover, we recently developed novel cerebral organoid and patient derived xenograft models for each subgroup of meningiomas. Our preliminary data presented in this application reveal convergent genetic mechanisms misactivating the cell cycle at the level of CDK6 in the subgroup of meningiomas with the worst clinical outcomes. Our central hypothesis is that CDK6 is required for meningioma growth, and that clinical CDK4/6 inhibitors will show activity in preclinical meningioma models. To test this hypothesis, we will define the efficacy and biomarkers of response to CDK4/6 inhibitors in meningioma, define the molecular mechanisms underlying CDK6 misactivation in meningiomas, and identify pathways mitigating resistance to CDK4/6 blockade in meningioma. Our proposal will integrate human samples, organoid models of meningioma tumorigenesis, and understudied patient derived xenografts with CRISPR interference and pharmacology. This approach is based on the premise that improving treatments for meningioma patients depends on our ability to identify and target key molecular mechanisms driving meningioma cell proliferation. We know surprisingly little about how meningiomas develop, and almost nothing about how to block the molecular mechanisms underlying meningioma growth. Though the short-term objective of this proposal is to broadly improve our understanding of meningioma cell proliferation, a long-term goal of this research is to understand this process well enough to develop targeted therapeutic strategies that will improve treatments and outcomes for meningioma patients. Thus, this work will not only explain how meningiomas grow, but will also elucidate druggable mechanisms and establish preclinical foundation to support new clinical trials for meningioma patients.