Improving pediatric brain tumor treatments using FLASH radiotherapy

PROJECT SUMMARY Our R01 application entitled, “Improving pediatric brain tumor treatments using FLASH radiotherapy” is focused on translating a novel irradiation modality into clinical practice. Here we will test whether radiation delivered in ultra-high dose rate (one-tenth of second), which far exceed the dose rate used in current clinical practice (minutes), can significantly reduce normal tissue toxicities associated with the radiotherapeutic management of childhood medulloblastoma (MB). The overarching goal is to alleviate the long term neurocognitive and cerebrovascular complications that compromise the quality of life of MB survivors while maintaining tumor control. To achieve these goals, we will undertake studies using clinically relevant FLASH and conventional radiation regimens. Two distinct human MB tumor models will be orthotopically implanted in the brain of nude mice to investigate simultaneously tumor response and neurocognitive function after irradiation. In addition, for long-term follow up, tumor-free mice will also be subjected to cranial irradiation using FLASH or conventional dose rate irradiation. Short-term (1-month) and longer term (4-6 months) studies conducted on tumor bearing and tumor free mice respectively, will critically evaluate tumor control, neurocognitive, cerebrovascular and molecular outcomes in these cohorts. Preclinical studies investigating the response of MB tumors, behavioral performance on multiple learning and memory tasks, vascular structure and integrity and the sparing of the neurogenic niche will unambiguously elucidate many of the mechanisms underlying the neuroprotective effects of FLASH radiotherapy. Data derived from these collaborative studies between UCI and the CHUV will facilitate the clinical translation of FLASH-RT to pediatric oncology, where despite the favorable prognosis of children diagnosed with MB, survivors still suffer a lifetime of complications caused by their prior radiotherapy, a scenario we hope to ameliorate with our innovative FLASH technology.