Project 2: Sparing in Tumor Free Animals

项目 2：保护无肿瘤动物

• 批准号: 10415035
• 负责人: Charles Limoli
• 金额: $ 36.24万
• 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/10415035
• 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; 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; Time; Tissues; Toxic effect; Translating; Translations; base; behavior test; behavioral outcome; cancer cell; cancer therapy; clinical practice; clinically relevant; cognitive function; 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 我们提议创建一个名为“提高脑肿瘤的治疗指数”的研究计划 通过创新的闪光放射疗法（FLASH-RT）进行治疗，重点是转化新型放射疗法（IR） 快速进入临床的总体假设是辐射是否以超高的速度进行。 剂量率（与当前临床实践中使用的低得多的剂量率相比）可以显着 改善正常组织并发症，同时保持可接受的肿瘤控制（如果没有改善）。 假设，该计划将部署一系列全面的临床前研究，这些研究将批判性地评估 FLASH-RT 和 FLASH-RT 后的肿瘤控制、神经认知结果以及由此产生的大脑辐射损伤 总的来说，这些研究将生成常规剂量率照射所需的数据集。 将新型 FLASH 照射平台快速转化为小鼠临床前研究。 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范式转变技术的潜在好处。 剂量测定/物理核心（核心 2）和 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、结构和免疫学研究 研究将阐明临床相关脑肿瘤治疗对患者的长期（长达 6 个月）影响 在严格控制的条件下对动物进行单组分 IR、多组分 IR 和 将对多分次 IR +/- TMZ 治疗臂进行行为测试，然后分析一些关键因素 对于这个项目，这些原理证明，神经元和血管的变化对于正确的认知功能至关重要。 必须在没有混杂疾病的情况下对无肿瘤动物进行长期神经认知研究， 并将为阐明 FLASH 提供的基础正常组织保护奠定基础 受辐射的大脑。