We respond here to a Funding Opportunity Announcement (FOA) for multi-institutional teams to form a Glioblastoma Therapeutics Network (GTN). Basic scientists and clinical/translational investigators from three institutions in the Dana-Farber/Harvard Cancer Center (DF/HCC) have joined forces with their counterparts in the Stanford Cancer Center (SCC) to create the “Harvard/Stanford GTN”. UT Southwestern is also represented in one key collaboration. Distinctive features of this bi-coastal GTN include (i) broad and deep expertise in brain-penetrant, small molecule therapeutics and (ii) a strong presence in the emerging field of Cancer Neuroscience – a field that addresses the central role of the nervous system in glioblastoma pathogenesis. Our objective is to improve the treatment of adult glioblastomas (GBMs) and Astrocytoma, IDH- mutant, grade 4 by taking novel, effective, brain-penetrant small molecule drugs through lead optimization, to preclinical development and into early phase clinical trials. Our study plan features three projects: Project 1 targets metabolic reprogramming in Astrocytoma, IDH mutant, grade 4. Project 2 targets the constitutive, ligand-independent EGFR signaling observed in more than 50% of adult IDH wild-type GBM. Project 3 targets a recently appreciated forward-feeding gliomagenic loop between tumor cells and electrically active neurons in IDH wild-type adult glioblastomas. All three projects feature surgical window clinical trials of brain-penetrant drugs that are hitherto untested in GBM. In addition, Project 2 will develop novel allosteric inhibitors that promise to address a shortcoming of all current EGFR antagonists as GBM therapeutics – to wit, lack of a therapeutic window. Insights from clinical trials will be enhanced by a Pharmacological and Genomic Imaging Core (PGIC). This core will allow our trialists to monitor drug impact on glioblastoma cell populations using specialized single cell RNAseq protocols. Drug penetrance within tumors and drug-induced changes in key metabolites will be visualized using matrix assisted laser desorption ionization mass spectrometry imaging and non-invasive magnetic resonance spectroscopy methodologies. In addition to these clinical/translational research projects and the PGIC, the Harvard/Stanford GTN offers to host a Network Coordinating Center (NCC) for the broader GTN initiative (as described and specified by the FOA). Our proposed NCC offers essential skill sets in neuropathology, cancer genetics, clinical trials, biostatistics, and clinical trial design that will enable multiple GTN centers to work together in ways that exceed the sum of their component parts. An Administrative Core will serve as the primary contact and communication resource for the Projects, the PGIC, an Internal Advisory Board, the NCC, the GTN Steering Committee, and NCI program officials. The Harvard/Stanford GTN Principal Investigator is Tracy Batchelor, M.D. an experienced clinical trialist with much ...