Neuro-Oncology Program Project Summary / Abstract Neuro-Oncology has been a CCSG disease-based Program since 2005, with the mission to improve standards of care for cancers of the nervous system. The Program features a broad portfolio of research initiatives in the general clinical disciplines and in therapeutically relevant scientific areas. Over the past two funding cycles, we prioritized work on astrocytomas – the most lethal brain tumor of adults and the most common brain tumor of childhood. Going forward, we will extend our work on astrocytomas and broaden our clinical and translational profile with an initiative on hereditary and sporadic neoplasms driven by loss-of-function mutations in the Neurofibromin 2 (NF2) gene. We will also explore new therapeutic opportunities from the emerging field of cancer neuroscience. In accord with the Director’s Strategic Vision, contemporary tools of medicinal chemistry will be brought to bear upon “undruggable” oncogenic drivers and tumor-specific, epigenetic, and metabolic vulnerabilities will be exploited as therapeutic targets. The immunosuppressive glioma microenvironment will be targeted with personalized, synthetic peptide neoantigen vaccines and with bi-valent CART cells that release anti-EGFR antibodies within the local environment of tumor cells. Skill sets of the leadership team (T. BatchelorBWH, D. Haas-KoganDFCI/BCH/BWH, S. PlotkinMGH, and M. SuvaMGH) align with Program strategies and research priorities. The Program’s 98 members (87 primary and 11 secondary) draw from all seven DF/HCC institutions and 15 academic departments. Peer-reviewed funding in 2019 was $13.1 M (direct costs, representing an increase from $12.2M reported in 2014), of which $8.9 M was from NCI. Components of the support package include a renewed SPORE grant on glioma a K12 training grant on Neuro Oncology. From 2016 to 2019, Program primary members generated 955 peer-reviewed publications. Inter-programmatic collaborations are reflected in 41% of these publications and intra- programmatic collaborations in 27%, while 26% represent inter-institutional collaborations. Going forward, we have five specific aims across the lifespan of central nervous system cancers. Aim one targets epigenetic vulnerabilities for diffuse midline glioma (DMG) - a uniformly fatal pediatric brain cancer. Aim two exploits “addictions” to druggable chromatin modifiers and metabolic pathways in grade 4 IDH-mutant astrocytomas of young adults. Aim three is to advance immunotherapy for IDH WT adult glioblastoma beyond the currently limited paradigm of immune checkpoint blockade. Aim four targets genetically validated protein kinases that may serve as downstream effectors of proliferation in NF2-deficient CNS tumors including meningiomas, schwannomas, and ependymomas. Aim five targets gliomagenic functions of microglia and electrically active neurons within the tumor microenvironment.