Purpose/Objective(s): Glioblastoma is a malignant brain tumor of the central nervous system that has median survival of 15-16 months. Radiation therapy is one of the major pillars of the current standard of care. However, radiation therapy may lead to serious sequelae such as endocrinopathies and cognitive impairment resulting from dose deposition in surrounding tissue. Ultra-high dose rate radiation therapy (FLASH) is a new method of radiation therapy that is thought to spare normal tissue while maintaining activity against tumor cells. We asked whether delivery of protons via FLASH would show comparable anti-tumor activity in a mouse model of glioma compared to standard dose rate proton therapy. Materials/Methods: We induced formation of primary glioblastomas of the proneural subtype by a retroviral vector carrying PDGFB and dominant negative p53 into the white matter of adult wildtype mice. This experiment (n Z 7 mice per group) included two irradiation groups and a control. Both irradiation groups received a single fraction of 10Gy but at different dose rates e 1Gy/s (conventional) and 100Gy/s (FLASH). The whole brain irradiations were performed on the plateau region of a high energy proton Bragg peak (100Gy/s at 250MeV, 1Gy/s at 244MeV). Results: We found that FLASH and conventional therapy both provided a statistically equivalent survival benefit in our endogenous glioblastoma model as compared to untreated animals. Following the initial tumor regression, we observed tumor relapse and re-growth for FLASH and conventional proton radiation based on MRI imaging. Dose escalation studies are ongoing to compare the curative potential of FLASH vs conventional irradiation in an endogenous glioma model. To understand the mechanisms by which tumors respond to FLASH vs conventional proton irradiation, we performed single-cell transcriptomic profiling on relapsed tumors treated with FLASH or conventional proton therapy and compared with untreated tumors. We found that proton radiation induced striking changes in the tumor microenvironment, specifically through an increase in myeloid derived suppressor cells. We have further characterized cell proliferation, apoptosis and tumor stem cell populations in relapsed tumors compared to untreated tumors and explored the differences in cellular responses with respect to FLASH or conventional proton irradiation. We will discuss transcriptomic profiling changes between pre-and post-proton treatment in the mouse glioma models. Conclusion: Our present work indicates that FLASH proton radiotherapy shows similar efficacy compared to conventional proton radiotherapy in an endogenous glioma model in immune-competent mice, and that tumor microenvironmental changes may contribute to tumor relapse.
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