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

• 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
• 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

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.

项目概要：总体 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，重点是转化一种新型放射疗法 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（如果没有改善的话）为了检验这一假设， 该计划将在 4 个项目中部署一系列全面的临床前研究，以评估效果 FLASH-RT 在肿瘤控制和神经认知方面的工作将在 3 个表演地点（CHUV、斯坦福大学、印第安纳州）进行。 实施传统和 FLASH 照射范例来评估每种辐射方式如何影响 GBM 原位荷瘤动物和无瘤动物的肿瘤控制、神经认知和相关病理学 （项目 1 和 2）在瑞士 CHUV 进行的一项临床试验将招募 GBM 狗患者进行评估。 使用 FLASH 方式增加剂量的治疗益处最后，每个表现部位将是。 参与通过改变照射过程中的氧张力来阐明 FLASH 效应的机制基础 重要的是，通过实施氧化还原敏感的转基因小鼠模型，这项工作将得到促进和促进。 由两个关键研究核心（剂量测定/物理学和神经行为）整合。 核心2，辐射剂量测定将交叉验证，技术创新将在所有领域实施 CHUV、斯坦福大学和印第安纳大学的辐射平台 在神经行为核心 3 中，动物。 在每个表演场地受到辐射的动物将被运送到 UCI，在那里动物将受到标准和 一系列精心控制的行为测试，旨在评估每次照射的效果 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。 该核心的总体目标是集中这些活动。 提高项目调查人员的运作效率和透明度。

项目成果

Radiation Research Special Issue: New Beam Delivery Modalities are Shaping the Future of Radiotherapy.

放射研究特刊：新的射束传输方式正在塑造放射治疗的未来。

• 发表时间: 2020
• 影响因子: 3.4
• 作者: Griffin, Robert J;Limoli, Charles L;Simone 2nd, Charles B
• 通讯作者: Simone 2nd, Charles B

Ultra-high dose rate electron beams and the FLASH effect: From preclinical evidence to a new radiotherapy paradigm.

超高剂量率电子束和闪光效应：从临床前证据到新的放射治疗范例。

• 发表时间: 2022-03
• 影响因子: 3.8
• 作者: Schüler, Emil;Acharya, Munjal;Montay;Loo Jr, Billy W;Vozenin, Marie;Maxim, Peter G
• 通讯作者: Maxim, Peter G

The sparing effect of FLASH-RT on synaptic plasticity is maintained in mice with standard fractionation.

在标准分级的小鼠中，FLASH-RT 对突触可塑性的保护作用得以维持。

• 发表时间: 2023-09
• 作者: Limoli, Charles L;Kramár, Eniko A;Almeida, Aymeric;Petit, Benoit;Grilj, Veljko;Baulch, Janet E;Ballesteros;Loo Jr, Billy W;Wood, Marcelo A;Vozenin, Marie
• 通讯作者: Vozenin, Marie

Evaluating the Reproducibility of Mouse Anatomy under Rotation in a Custom Immobilization Device for Conformal FLASH Radiotherapy.

评估用于适形闪光放射治疗的定制固定装置中旋转下小鼠解剖结构的再现性。

• 发表时间: 2020
• 影响因子: 3.4
• 作者: Ko, Ryan B;Soto, Luis A;von Eyben, Rie;Melemenidis, Stavros;Rankin, Erinn B;Maxim, Peter G;Graves, Edward E;Loo, Billy W
• 通讯作者: Loo, Billy W

Implementation and validation of a beam-current transformer on a medical pulsed electron beam LINAC for FLASH-RT beam monitoring.

在医用脉冲电子束 LINAC 上实现和验证束电流互感器，用于 FLASH-RT 束监测。

• 发表时间: 2021-11
• 作者: Oesterle, Roxane;Gonçalves Jorge, Patrik;Grilj, Veljko;Bourhis, Jean;Vozenin, Marie;Germond, Jean;Bochud, François;Bailat, Claude;Moeckli, Raphaël
• 通讯作者: Moeckli, Raphaël