Project summary This is the renewal application of a SPORE initiative from Dana-Farber/Harvard Cancer Center. We focus on gliomas of children and young adults. Our objective is to develop therapies targeted to oncogenic drivers and/or oncogene-induced vulnerabilities of these tumors. Towards these ends, basic scientists join with clinician scientists from Boston Children’s Hospital, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital. There are three projects: Project one targets pediatric low-grade gliomas (pLGGs). Nearly 75% of pLGGs are driven by truncation/fusion variants of the BRAF protein kinase. The project one team has made significant contributions to development of tovorafenib – a brain penetrant type 2 RAF inhibitor that is effective on all common BRAF oncoproteins. For this renewal application, the goals of project one are to reduce variability in response to RAF inhibitors such as tovorafenib and develop non-invasive “child friendly” tools to predict children most likely to require (and respond to) these drugs. Project two targets diffuse midline gliomas (DMGs) – the deadliest brain tumor of children. DMGs cannot be cured by conventional therapeutic modalities and the prevalent oncogenic drivers are undruggable. During the current funding period, the project two team has identified a synthetic lethal “addiction” to the alternate end joining pathway for DNA repair (“alt-EJ”) and identified brain-penetrant drugs that specifically target this pathway. Going forward, the goal of project two is to exploit alt-EJ repair antagonists as targeted therapeutics for DMG. Project three addresses the early-stage (lower- grade) IDH mutant gliomas (hereafter termed “IDHM”) of young adults. During the current funding period, the project team identified synthetic lethal vulnerabilities for the more aggressive (WHO grade 4) IDHM gliomas. Going forward, the goal of project three is to integrate these synthetic lethal therapeutic opportunities for grade 4 IDHM glioma into “the vorasidenib era” that has been opened by the recent clinical studies on early stage (grade 2) IDHM gliomas of young adults. The study plan employs contemporary methods in structural biology, cancer genomics, computer science and machine learning. Each project has a human endpoint, and two projects will involve clinical trials. Rigor and reproducibility of work will be fostered by cores for Pathology and for Biostatistics. An Administration core will enable and manage the multiple consortium agreements and collaborative interactions Harvard Medical School, the four participating Harvard teaching hospitals and facilitate clinical trials and imaging studies. Intellectual vigor within the program is sustained and refreshed by annual Career Enhancement Awards to young investigators and by annual Developmental Project Awards.