Principal Institutions: Dana Farber Cancer Institute in partnership with the Pacific Pediatric Neuro Oncology Consortium (PNOC).  Oncogenic dysregulation of the RAS/RAF/MEK/ERK pathway has been described in a number of diverse malignancies, including low grade gliomas. Furthermore, mutations in BRAF, which occur in both monomeric and dimeric forms, drive the majority of pediatric LGG. Yet, only ten percent of pediatric LGGs possess BRAF V600E mutations, some of which are targetable by current type I inhibitors (dabrafenib, vemurafenib), which bind the activation site of the V600E mutation to prevent downstream signaling. The application of type I inhibitors to the majority of patients whose tumors do not possess V600E mutations was met with disappointment and in many cases deleterious results due to the unexpected acceleration of tumor growth in treated patients – a result brought about by paradoxical ERK activation in a process termed negative cooperativity. Current therapies for this patient group now target the downstream MEK and MTOR signaling molecules but have yielded responses in only a small subset of patients likely due to poor CNS penetration and downstream location. A promising new class of inhibitors, however, targets all mutations of BRAF, including the much more common dimerizing forms of mutant BRAF, as exemplified by the common KIAA1549:BRAF fusion duplication. This class of BRAF inhibitor (called type II) functions via a completely different mechanism of action via stabilization of the BRAF/MEK complex. Our preclinical results supported by our Brain SPORE grant (Project 4; PIs Kieran and Eck) demonstrated that this inhibitor has excellent CNS penetration as demonstrated by scanning MALDI-TOF analysis, is effective on all BRAF point mutations (not just BRAF V600E) as well as all truncated fusion forms of BRAF and that by virtue of the RAF/MEK complex stabilization, prevents the paradoxical activation that occurs with all type I inhibitors currently available. Clinical trials of these drugs in adults have laid the foundation for moving forward with testing in children, thereby positioning us to design the first trial to test such a novel pathway inhibitor for the most common pediatric brain tumor. TAK-580, a type II inhibitor with excellent CNS penetration and documented activity demonstrated in a number of LGG models based on the work done at our institution, is the focus of our upcoming trial. The trial design includes phase 1, 2 and target validation arms, the latter providing the opportunity to verify CNS penetration in patient tumors and evaluate pre- and post-treatment biopsy samples to study pathway inhibition and possible resistance among unresponsive tumors. This drug has the potential to transform treatment for the majority of patients with the most common pediatric tumor, a tumor for which surgery is often not possible and treatment morbidity high.