Improving pediatric brain tumor treatments using FLASH radiotherapy

项目摘要 我们的R 01申请题为“使用FLASH放射疗法改善儿科脑肿瘤治疗”， 专注于将一种新的放射疗法转化为临床实践。在这里，我们将测试辐射是否 以超高剂量率（十分之一秒）输送，远远超过目前临床上使用的剂量率。 实践（分钟），可以显着减少与放射性相关的正常组织毒性 儿童髓母细胞瘤（MB）的管理。首要目标是缓解长期 神经认知和脑血管并发症损害MB幸存者的生活质量， 维持肿瘤控制。为了实现这些目标，我们将使用临床相关的FLASH进行研究 和常规的放射疗法。将原位植入两种不同的人MB肿瘤模型 在裸鼠的脑中同时研究肿瘤反应和神经认知功能， 辐照此外，为了长期随访，无肿瘤小鼠也将接受颅脑照射 使用FLASH或常规剂量率照射。短期（1个月）和长期（4-6个月）研究 分别在荷瘤和无瘤小鼠中进行，将严格评价肿瘤控制， 这些队列的神经认知、脑血管和分子结果。临床前研究 MB肿瘤的反应，多个学习和记忆任务的行为表现，血管结构和 神经原性生态位的完整性和保留将明确阐明许多机制 这是FLASH放疗的神经保护作用的基础。从这些合作研究中获得的数据 UCI和CHUV之间的合作将有助于将FLASH-RT临床转化为儿科肿瘤学， 尽管确诊患有MB的儿童预后良好，但幸存者仍会遭受终生的并发症 我们希望通过我们的创新FLASH技术来改善这种情况。

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.