Optimization of MeV FLASH radiotherapy for normal tissue preservation

MeV FLASH 放射治疗对正常组织保存的优化

• 批准号: 10366743
• 负责人: David J. Gladstone
• 金额: $ 64.22万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-06 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366743
• 关键词: Address; Adoption; Animals; Area; Basic Science; Beds; Biochemistry; Biological Assay; Biology; Biomedical Engineering; Brain; Breast Lymphoma; Canis familiaris; Chemistry; Clinical; Colon; Consumption; DNA Damage; Data; Devices; Doctor of Philosophy; Dose; Dose-Rate; Effectiveness; Electron Spin Resonance Spectroscopy; Engineering; Ensure; Free Radicals; Future; Genetic; Head and neck structure; Human; Hypoxia; Image; In Situ; In Vitro; International; Iowa; Iron; Link; Lung; Malignant Neoplasms; Measurement; Measures; Methods; Molecular; Morphology; Normal tissue morphology; Norris Cotton Cancer Center; Optics; Oxygen; Oxygen saturation measurement; Pathology; Pathway interactions; Patients; Performance; Physics; Physiologic pulse; Production; Proteomics; Publications; Radiation; Radiation Dose Unit; Radiation Genetics; Radiation Oncology; Radiation Physics; Radiation induced damage; Radiation therapy; Radiobiology; Radiochemistry; Reaction; Reactive Oxygen Species; Research; Research Project Grants; Risk; Running; Schools; Skin; System; Techniques; Therapeutic; Therapeutic Effect; Tissue Preservation; Tissues; Translations; Tumor Tissue; United States National Institutes of Health; Validation; Work; base; cell killing; design; dosimetry; first-in-human; gastrointestinal; in vivo; instrumentation; internal radiation; irradiation; luminescence; mouse model; open source; oxidation; pre-clinical; preservation; programs; prototype; radiation effect; repaired; tissue oxygenation; tool; treatment comparison; treatment planning; tumor

ABSTRACT Significant improvement in the effectiveness of radiation therapy (RT) now seems possible because of recent exciting research results using ultra-high dose rates (UHDR), indicating that normal tissue damage can be reduced (the `FLASH' effect), compared to conventional radiation for the same total dose. FLASH RT delivery has shown reduced morphological and functional damage to normal tissues such as brain, colon, lung, and skin. Although significant research remains, early indications are that the normal tissue sparing effect may as high 50% at some dose levels. If proven in translation, this effect would be the most significant improvement in RT therapeutic ratio since the advent of treatment planning. While intriguing mechanisms for this result have been postulated, they remain only well-reasoned speculations because of a lack of direct in vivo data on the physico- chemical mechanisms including oxygen depletion and free radical species alterations. Dartmouth has created the first reversible MeV FLASH beam on a clinically commissioned linac with >100 Gy/s at the patient treatment bed, and prototyped an open-source treatment planning system, expanding research access. Additionally, the team has invented unique technological capabilities to directly measure the highest dose rates and in vivo tissue oxygen transients. The key technological barriers solved in the proposed research with preliminary data are: 1) demonstration of conversion to a UHDR irradiator within a clinically commissioned linac, 2) verification of per- pulse and per-fraction dose rates, 3) direct in vivo observation of oxygen transients, 4) direct measurements of free radical species changes in vitro, and 5) access to functional tissue assays and genetic and proteomic assays. Single-pulse and single-fraction dose rates will be quantified by high frame rate imaging. Additionally, the in vivo oxygen changes will be quantified by two independent methods for co-validation, including electron paramagnetic resonance oximetry and optical luminescence oximetry. Free radical species changes produced from transient hypoxia will also be assessed through systematic in vitro analyses, and the potential linkages to functional, proteomic and DNA damage examined. The FLASH beam conditions that minimize normal tissue damage for a fixed dose will be established with this baseline data. The work is pre-clinical but can be readily adapted to ongoing NIH sponsored spontaneous canine cancer studies has relevance to future large animal and first-in-human translation. Multiple Dartmouth centers partnered to initiate and support this FLASH program. Taken altogether, this bioengineering research project will advance the state of the art in high dose rate radiation therapy using tools that have been uniquely developed by our 3 research groups, and the project results will build the basic science needed to support proposed human translation of this ground-breaking field. The team has leading expertise in radiation physics, in vivo molecular measurement, and radiation genetics and immunomolecular biology and pathology. The work is supported by an External Advisory Board of international expert FLASH consultants, as well as an internal Radiation Oncology Advisory Group.

抽象的 现在似乎可以显着提高放射治疗（RT），因为最近 使用超高剂量率（UHDR）的令人兴奋的研究结果，表明正常的组织损伤可能是 与相同总剂量的常规辐射相比，降低（“闪光”效应）。 Flash RT交付 已经显示出对正常组织（例如大脑，结肠，肺和皮肤）的形态和功能损害降低。 尽管仍然有重大研究，但早期的迹象表明，正常的组织保留效应可能很高 在某些剂量水平上有50％。如果经过翻译证明，这种效果将是RT的最大改善 治疗计划出现以来的治疗比率。虽然这个结果的有趣机制是 假设，由于缺乏有关物理学的直接体内数据，它们仍然只是众多的猜测 化学机制，包括氧耗竭和自由基物种改变。达特茅斯创造了 在患者治疗时，在临床上委托的Linac上的第一个可逆MEV闪光灯横梁，> 100 gy/s 床，并原型开源治疗计划系统，扩大了研究访问。另外， 团队发明了独特的技术能力，可以直接测量最高剂量率和体内组织 氧瞬变。在提议的研究中使用初步数据解决的关键技术障碍是：1） 在临床上委托的Linac中向UHDR辐照器转换为UHDR辐照器的演示，2） 脉冲和人均剂量率，3）直接在体内观察氧瞬变，4）直接测量 自由基物种在体外变化，以及5）获得功能组织分析以及遗传和蛋白质组学的获取 测定。单脉冲和单分数剂量率将通过高框架速率成像来量化。此外， 体内氧的变化将通过两种独立的共同验证方法来量化，包括电子 顺磁共振血氧仪和光发光血氧仪。产生的自由基物种变化 还将通过系统的体外分析来评估瞬态缺氧，并将潜在的联系与 检查了功能，蛋白质组学和DNA损伤。闪光灯条件可最大程度地减少正常组织 使用此基线数据将确定固定剂量的损害。这项工作是临床前的，但很容易 适用于正在进行的NIH赞助的自发犬类癌症研究与未来的大动物和 人类的第一笔翻译。多个达特茅斯中心合作启动和支持此Flash计划。 完全采用的生物工程研究项目将在高剂量辐射中推进最新技术 使用我们的3个研究小组独特开发的工具的治疗，项目结果将 建立支持该开创性领域的人类翻译所需的基础科学。团队 在辐射物理学，体内分子测量和辐射遗传学以及 免疫分子生物学和病理学。这项工作得到了国际外部顾问委员会的支持 专家Flash顾问以及内部辐射肿瘤学咨询小组。