Improving pediatric brain tumor treatments using FLASH radiotherapy

项目总结 我们的R01应用程序名为“使用闪光放射治疗改善儿童脑肿瘤的治疗”， 专注于将一种新的照射方式转化为临床实践。在这里我们将测试辐射是否 超高剂量率(十分之一秒)，远远超过目前临床使用的剂量率 练习(分钟)，可以显著减少与放射治疗相关的正常组织毒性 儿童髓母细胞瘤(MB)的治疗最重要的目标是缓解长期 神经认知和脑血管并发症危及MB幸存者的生活质量 维持肿瘤控制。为了实现这些目标，我们将使用与临床相关的闪存进行研究 和常规的放射疗法。两种不同的人类MB肿瘤模型将被原位植入 在裸鼠脑内同时观察肿瘤反应和神经认知功能 辐射。此外，为了长期随访，无瘤小鼠还将接受颅脑照射 采用闪光或常规剂量率照射。短期(1个月)和长期(4-6个月)研究 分别在有瘤小鼠和无瘤小鼠上进行，将对肿瘤控制进行批判性评估， 这些队列中的神经认知、脑血管和分子结果。临床前研究调查 MB肿瘤的反应，在多个学习和记忆任务中的行为表现，血管结构和 神经源性小生境的完整性和节制将明确地阐明许多机制。 闪光放射治疗的神经保护作用。从这些协作研究中获得的数据 UCI和CHUV之间的合作将促进Flash-RT向儿童肿瘤学的临床转换，其中 尽管被诊断患有MB的儿童预后良好，但幸存者仍然遭受终生并发症的折磨 由于他们之前的放射治疗，我们希望通过我们的创新闪存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.