Increasing the therapeutic index of brain tumor treatment through innovative FLASH radiotherapy

项目概要：总体 我们建议创建一个研究项目，题为“提高脑肿瘤的治疗指数 通过创新的FLASH放射治疗（FLASH-RT），专注于将一种新的放射疗法 快速进入临床。要检验的总体假设是， 剂量率（与当前临床实践中使用的低得多的剂量率相比）可以显著改善 正常的组织并发症，同时保持可接受的，如果没有改善的肿瘤控制。为了验证这个假设， 该计划将在4个项目中部署一系列全面的临床前研究， FLASH-RT对肿瘤控制和神经认知的影响。在3个表演场地（CHUV、斯坦福大学、印第安纳州）工作将 实施常规和FLASH照射范例，以评估每种放射方式如何影响GBM 原位荷瘤和无瘤动物的肿瘤控制、神经认知和相关病理 （项目1和2）。在瑞士CHUV进行的一项临床试验将招募GBM狗患者进行评估 使用FLASH模式的剂量递增的治疗益处。最后，每个表演场地将 参与阐明通过改变照射过程中的氧分压来产生闪光效应的机制基础 以及通过实施氧化还原敏感的转基因小鼠模型。重要的是，这项工作将得到促进， 由两个关键的研究核心（剂量学/物理学和神经行为学）整合。在剂量学和物理学中 核心2，辐射剂量测定将进行交叉验证，技术创新将在所有 CHUV、斯坦福大学和印第安纳州大学的辐照平台。在神经行为核心3中，动物 将在每个性能研究中心接受辐照的动物运送至UCI，在那里动物将接受标准和 一系列精心控制的行为测试，旨在评估每次照射 范式在功能上影响认知。行政核心将作为所有人的组织中心 科学和方案活动。该核心的总体目标是集中这些活动， 提高业务效率和项目调查人员的透明度。

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.