Project 2: Sparing in Tumor Free Animals

项目 2：保护无肿瘤动物

• 批准号: 10652600
• 负责人: Charles Limoli
• 金额: $ 23.01万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652600
• 关键词: Acute; Aftercare; Animals; Behavioral; Blood Vessels; Brain; Brain Neoplasms; Canis familiaris; Chronic; Clinic; Clinical; Clinical Trials; Cognition; Cognitive; Coupled; Data; Data Set; Development; Disease; Dose; Dose Limiting; Dose Rate; Electron Beam; Exhibits; Foundations; Glioblastoma; Goals; Immunologics; Impaired cognition; Inflammation; Inflammatory; Knowledge; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Medical; Modality; Molecular; Morphology; Mus; Neurocognitive; Neurons; Normal tissue morphology; Oncologist; Outcome; Oxidation-Reduction; Oxygen; Patients; Pediatric cohort; Physics; Prognosis; Quality of life; Radiation; Radiation Injuries; Radiation therapy; Radiation-Induced Change; Research; Research Design; Series; Structure; Survivors; Technology; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Translating; Translations; behavior test; behavioral outcome; cancer cell; cancer therapy; clinical practice; clinically relevant; cognitive function; comparison control; conventional dosing; dosimetry; immunoregulation; improved; indexing; innovation; insight; irradiation; mouse model; neurobehavioral; neurobiological mechanism; neuroinflammation; neurotransmission; novel; pre-clinical; preclinical study; programs; radiation delivery; side effect; single fraction radiation; temozolomide; tissue injury; translational impact; treatment arm; tumor; weapons

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.

项目摘要 - 项目2 我们提出了一个名为“增加脑肿瘤的治疗指数”的研究计划的创建 通过创新的闪光放射疗法（Flash-RT）的治疗，重点是翻译新型辐射（IR） 模态迅速进入诊所。要测试的总体假设是辐射是否在超高处传递 剂量率（与当前临床实践中使用的剂量率较低相比）可以显着 减轻正常组织并发症，同时保持可接受的肿瘤控制。测试这个 假设，该计划将部署一系列全面的临床前研究，以批判性评估 在闪存-RT和 常规剂量率照射。总的来说，这些研究将生成所需的数据集 新型闪光照射平台的快速翻译为临床情况。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 辐射损伤的氧气依赖性机制与GBM狗患者的临床试验结合到 告知肿瘤学家这种潜在范式转移技术的潜在好处。目标 该计划项目将由剂量法/物理核心（核心2）和 神经行为核心（核心3）。 当前的项目（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影响（最长6个月）的研究 认知在精心控制的条件下。受到单位分数IR，Multfaction IR的动物和 多算法IR +/- TMZ治疗臂将在行为上测试，然后分析一些关键 神经元和血管变化对于适当的认知功能必不可少。对于这个项目，这些原理证明， 在没有混杂疾病的情况下，必须在无肿瘤动物中进行长期神经认知研究， 并将为阐明闪光灯提供的基础阐明正常组织的基础 辐照大脑。