Primary brain tumors in adults represent a heterogeneous and often fatal group of tumors. Current treatment of primary brain tumors heavily relies on surgery, radiation, and chemotherapy and is associated with cognitive impairment and other toxicities. Unlike in many other human cancers, inhibitors of oncogenic kinases have shown inconsistent clinical activity in brain tumor patients and it remains unclear which genetic alterations are critical for tumor maintenance in specific brain tumor types. The goal of this research program is to establish therapeutic strategies that exploit the most common genetic alterations is three specific tumor types, namely mutant isocitrate dehydrogenase (IDH) in low grade glioma, Bruton's Tyrosine Kinase (BTK) in Primary CNS Lymphoma (PCNSL), and EGFR in glioblastoma (GBM). Our research program incorporates the evaluation of tumor biopsies from patients being treated with inhibitors of these pathways, genetic and pharmacological studies in newly-derived experimental brain tumor models, and the development of state-of-the art approaches to quantify intratumoral heterogeneity in cancer signaling and tumor evolution. We believe that our research program will narrow the current knowledge gap regarding oncogene “addiction” in primary brain tumors and provide a framework for mechanism-based combination therapies targeting these signaling nodes and other signaling pathways.