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

通过创新FLASH放射治疗提高脑肿瘤治疗的治疗指数

基本信息

批准号：
10652596
负责人：
Charles Limoli
金额：
$ 153.81万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
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/10652596
关键词：
Aftercare Animals Autopsy Brain Brain Neoplasms Canis familiaris Cause of Death Characteristics Chemicals Clinic Clinical Clinical Management Cognition Combined Modality Therapy Conduct Clinical Trials Data Dose Dose Limiting Dose Rate Electron Beam Electrons Evaluation Follow-Up Studies Glioblastoma Glioma Goals Histologic Human Hydrogen Peroxide Hypoxia Immunologics Impaired cognition Indiana Inflammation Investigation Ions Irradiated tumor Lipid Peroxidation Malignant Neoplasms Malignant neoplasm of brain Metals Metastatic malignant neoplasm to brain Modality Modeling Molecular Nature Neurocognition Neurocognitive Neurons Normal tissue morphology Organ Oxidation-Reduction Oxygen Pathology Patients Physics Physiological Protocols documentation Radiation Radiation Dose Unit Radiation Oncology Radiation Protection Radiation therapy Radiation-Induced Change Radiobiology Radiometry Research Research Personnel Rodent Roentgen Rays Role Safety Series Standardization Structure Switzerland Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Transgenic Mice Translating Translations Treatment Protocols Tumor Tissue Universities Work behavior test cancer cell cancer type clinical implementation clinical practice conventional dosing design dosimetry follow-up functional outcomes genetic approach glutathione peroxidase high risk improved innovation irradiation metal chelator mouse model neurobehavioral neurobiological mechanism neurocognitive test neuroinflammation novel operation oxidative damage oxygen toxicity performance site pharmacologic preclinical study programs radiation delivery recruit response standard care technological innovation temozolomide treatment optimization tumor tumor progression virtual

项目摘要

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.

项目摘要：总体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）进行处理，重点是翻译新型辐射模态迅速进入诊所。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）可以显着改善正常的组织并发症，同时保持可接受的肿瘤控制。为了检验这一假设，该计划将在四个项目中部署一系列临床前研究，以评估效果在肿瘤控制和神经认知方面的闪存。在3个表演网站（Chuv，Stanford，Indiana）工作将实施常规和闪光照射范例，以评估每种辐射方式如何影响GBM 原位肿瘤轴承和无肿瘤动物的肿瘤控制，神经认知和相关病理（项目1和2）。在瑞士CHUV进行的临床试验将招募GBM狗患者评估使用闪光灯模态剂量升级的治疗益处。最后，每个性能网站将是通过改变辐射过程中的氧张力来阐明闪光效应的机械基础并通过实现氧化还原敏感的转基因小鼠模型。重要的是，这项工作将做好准备，并且由两个关键的研究核心（剂量法/物理学和神经行为）整合。在剂量和物理学中核心2，辐射剂量测定将进行交叉验证，并且将在所有人中实施技术创新 CHUV，斯坦福大学和印第安纳大学的辐照平台。在神经行为核心3中，动物在每个性能地点受辐照的地点将运送到UCI，在那里将遵守标准和旨在评估每种辐射的综合控制行为测试的全面电池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程序化活动。该核心的总体目标是集中这些活动促进计划调查人员的操作效率和透明度。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Response to Ling et al. regarding "An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses".

DOI：
10.1016/j.radonc.2020.03.001
发表时间：
2020-06
期刊：
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
影响因子：
0
作者：
Buettner GR;Spitz DR;Limoli CL
通讯作者：
Limoli CL

A rigorous behavioral testing platform for the assessment of radiation-induced neurological outcomes.

用于评估辐射引起的神经系统结果的严格行为测试平台。