PROJECT SUMMARY: OVERALL We are proposing the creation of a research program entitled, “Increasing the therapeutic index of brain tumor treatment through innovative FLASH radiotherapy (FLASH-RT), focused on translating a novel irradiation modality rapidly into the clinic. The overall hypothesis to be tested is whether radiation delivered at ultra high dose rates (compared to the much lower dose rates used in current clinical practice) can significantly ameliorate normal tissue complications while maintaining acceptable if not improved tumor control. To test this hypothesis, the program will deploy a comprehensive series of preclinical studies across 4 projects that will evaluate effects of FLASH-RT on tumor control and neurocognition. Work at 3 performance sites (CHUV, Stanford, Indiana) will implement conventional and FLASH irradiation paradigms to evaluate how each radiation modality impacts GBM tumor control, neurocognition and associated pathologies in orthotopic tumor bearing and tumor free animals (Projects 1 and 2). A clinical trial conducted at the CHUV in Switzerland will recruit GBM dog patients to evaluate the therapeutic benefits of dose escalation using the FLASH modality. Lastly, each performance site will be involved in elucidating the mechanistic basis of the FLASH effect by altering oxygen tension during irradiation and by implementing redox sensitive transgenic mouse models. Importantly, this work will be facilitated and integrated by two critical research cores (dosimetry/physics and neurobehavioral). In the Dosimetry and Physics Core 2, radiation dosimetry will be cross-validated and technological innovation will be implemented across all irradiation platforms at the CHUV, Stanford and Indiana University. In the Neurobehavioral Core 3, animals irradiated at each performance site will be shipped to UCI where animals will be subjected to a standard and comprehensive battery of carefully controlled behavioral tests designed to evaluate how each irradiation paradigm functionally impacts cognition. The Administrative Core will serve as the organizational hub for all scientific and programmatic activities. The overall goal of this Core will be to centralize these activities while promoting efficiency in operations and transparency for the program investigators.