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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：
10415033
负责人：
Charles Limoli
金额：
$ 222.23万
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/10415033
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 Pharmacology 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 Ships 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 design dosimetry follow-up functional outcomes genetic approach glutathione peroxidase high risk innovation irradiation metal chelator mouse model neurobehavioral neurobiological mechanism neurocognitive test neuroinflammation novel operation oxidative damage oxygen toxicity performance site 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.

项目总结：总体