Project 2: Sparing in Tumor Free Animals

项目摘要--项目2 我们建议建立一个研究项目，名为“提高脑瘤的治疗指数”。 通过创新的闪光放射治疗(闪光-RT)，重点是转化一种新的照射(IR) 医疗模式迅速进入临床。要检验的总体假设是，辐射是否在超高辐射下传递 剂量率(与当前临床实践中使用的低得多的剂量率相比)可以显著地 改善正常组织并发症，同时保持可接受的肿瘤控制，如果不是改善的话。为了测试这一点 假设，该计划将部署一系列全面的临床前研究，这些研究将对 闪光放射治疗后肿瘤控制、神经认知结果和由此导致的脑辐射损伤 常规剂量率照射。总的来说，这些研究将产生所需的数据集 将新型闪光照射平台快速转化为临床方案。小鼠的临床前研究 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 辐射损伤的氧依赖机制与对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换技术的潜在好处。目标 本方案项目的执行将由剂量学/物理学核心(核心2)开展的活动提供便利 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、结构和免疫学 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。接受单组分IR、多组分IR和 多组分IR/-TMZ治疗臂将进行行为测试，然后分析一些关键的 神经元和血管的变化是正常认知功能所必需的。对于这个项目，这些主体证明， 长期的神经认知研究必须在没有混杂疾病的无肿瘤动物身上进行， 为阐明闪光对正常组织的保护作用奠定了基础。 受过辐射的大脑。

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.