Project 2: Sparing in Tumor Free Animals

项目概要-项目2 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（IR） 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 改善正常组织并发症，同时保持可接受的（如果不是改善的）肿瘤控制。为了验证这一 假设，该计划将部署一系列全面的临床前研究，将严格评估 肿瘤控制、神经认知结果和FLASH-RT后对大脑的放射损伤， 常规剂量率辐照。总的来说，这些研究将产生必要的数据集， 将新型FLASH辐照平台快速转化为临床场景。小鼠临床前研究 评估原位肿瘤控制、认知、神经元和血管结构可塑性、免疫调节 放射损伤的氧依赖性机制与GBM犬患者的临床试验相结合， 告知肿瘤学家这种潜在的范式转变技术的潜在好处。目标 将通过剂量测定/物理学核心（核心2）开展的活动促进本计划项目的实施， 神经行为核心（核心3）。 目前的项目（项目2）涉及一系列全面的认知，结构和免疫 将阐明临床相关脑肿瘤治疗的长期（长达6个月）影响的研究 在严格控制的条件下进行认知。动物接受单次IR、多次IR和 将对多部分IR +/- TMZ治疗组进行行为学测试，然后分析一些关键的 神经元和血管的变化对正确的认知功能至关重要。对于这个项目，这些主要的证明， 长期的神经认知研究必须在没有混杂疾病的无肿瘤动物中进行， 并将为阐明FLASH提供的正常组织保留的基础提供基础。 辐射过的大脑

PROJECT SUMMARY – PROJECT 2 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 (IR) 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 that will critically evaluate tumor control, neurocognitive outcomes and resultant radiation injury to the brain following FLASH-RT and conventional dose rate irradiation. Collectively, these studies will generate the requisite data sets required for the rapid translation of the novel FLASH irradiation platform to the clinical scenario. Preclinical studies in mice assessing orthotopic tumor control, cognition, neuronal and vascular structural plasticity, immune-modulation and oxygen dependent mechanisms of radiation injury are coupled with a clinical trial in GBM dog patients to inform the oncologists of the potential benefits of this potentially paradigm shifting technology. The objectives of this program project will be facilitated by the activities conducted by the dosimetry/physics core (Core 2) and the Neurobehavioral Core (Core 3). The current project (Project 2) involves a comprehensive series of cognitive, structural and immunological studies that will elucidate the long-term (up to 6 months) impact of clinically relevant brain tumor treatments on cognition under carefully controlled conditions. Animals subjected to single fraction IR, multifraction IR, and multifraction IR +/- TMZ treatment arms will be behaviorally tested then analyzed for some of the critical neuronal and vascular changes essential for proper cognitive function. For this project, these proof-of-principal, long-term neurocognitive studies must be made in tumor free animals in the absence of confounding disease, and will provide the foundation for elucidating the basis normal tissue sparing afforded by FLASH in the irradiated brain.