Translational Studies in FLASH Particle Radiotherapy

项目摘要 放射疗法（RT）用于治疗许多癌症，包括肉瘤和肺癌， 胰腺癌尽管在过去几十年中取得了重大进展，但仍有很大的空间， 改善，因为患者仍然发展RT诱导的损伤或第二恶性肿瘤。FLASH放疗， 其以超高剂量率递送大剂量辐射，可以潜在地降低毒性。我们的整体 假设质子/碳粒子FLASH RT在保护方面优于标准粒子RT， 正常组织，而这两种模式在控制恶性生长方面是等效的。 项目1侧重于胰腺癌，将确定剂量和生物物理参数， 使用FLASH质子治疗（F-PRT）将最大限度地保留正常肠组织， 抗肿瘤作用它将描绘正常肠组织的不同反应的机制方面， 集中于干/祖细胞群体的相对保留。项目1也将采用p53 +/-转基因 用于剖析标准质子治疗（S-PRT）的不同GI毒性的遗传决定因素的小鼠模型 相对于F-PRT。项目2将探索F-PRT改善不良事件（炎症，纤维化， 水肿、骨结构变化、辐射诱发的癌症），这些疾病对治疗 我们还将进行一项1/2期试验，将治疗患有骨肉瘤的犬患者 最终与F-PRT。项目3将比较FLASH-RT与碳离子放射治疗（C- RT）与标准剂量率，并将其与电子F-RT进行比较。研究将侧重于正常组织的缓解 NSCLC中的损伤，重点是正常组织和肿瘤内缺氧对以下反应的影响 最后，项目4将开发和验证笔形束扫描（PBS）技术在粒子成像中的应用。 它将分析时空变化和SOBP（扩展布拉格峰）与通过PBS拍摄， 开发剂量输送算法，用于对基于PBS的FLASH质子治疗的生物效应进行建模。这些 这些工具将纳入项目1 - 3的实验计划。这些项目由4个核心支持 包括管理核心（核心A）、物理剂量核心（核心B），它们将提供基础设施 协调不同部位之间的剂量测定和组织比较病理学核心（核心C）的服务 组织病理学评价准备。统计服务将由核心D提供。 总的来说，由辐射和肿瘤生物学领域公认的领导者领导的这一高度综合的努力旨在 定义生物学、剂量学和生物物理学参数以及FLASH RT在我们认为最有可能首先在临床试验中进行测试的肿瘤和组织中最有效。是我们 相信只有通过获得这些知识，这种令人兴奋的和新颖的形式才能被引入 以安全有效的方式改善癌症患者的治疗效果和生活质量。

PROJECT SUMMARY Radiation therapy (RT) is used in the curative setting for many cancers including sarcomas and lung and pancreatic cancer. Despite significant improvements over the past few decades, there is still much room for improvement as patients still develop RT-induced injuries or second malignant neoplasms. FLASH radiotherapy, which delivers a large dose of radiation at an ultra-high dose rate could potentially reduce toxicity. Our overall hypothesis is that Proton/Carbon Particle FLASH RT is superior to Standard Particle RT in protecting normal tissues while the two modalities will be equipotent in controlling malignant growth. Project 1, which focuses on pancreatic cancer, will define the dosimetric and biophysical parameters that will maximally spare normal intestine tissues using FLASH proton therapy (F-PRT) without compromising antitumor effects. It will delineate mechanistic aspects of differential response of normal intestinal tissues, by focusing on the relative sparing of the stem/progenitor cell population. Project 1 will also employ p53+/- transgenic mouse models to dissect the genetic determinants of differential GI toxicity of Standard proton therapy (S-PRT) vs F-PRT. Project 2 will explore the ability of F-PRT to ameliorate adverse events (inflammation, fibrosis, lymphedema, changes to bone structure, radiation-induced cancers) that pose barriers to the treatment of sarcomas with RT. We will also carry out a phase 1/2 trial that will treat canine patients with osteosarcomas definitively with F-PRT. Project 3 will compare the efficacy of FLASH-RT given with carbon ion radiotherapy (C- RT) vs. standard dose rate and compare it to electron F-RT. Studies will focus on the mitigation of normal tissue injury in NSCLC with an emphasis on the impact of normal tissue and intratumoral hypoxia to response following C-RT. Lastly, Project 4 will develop and validate the use of pencil beam scanning (PBS) technology for particle F-RT. It will analyze spatiotemporal variations and SOBP (spread out Bragg peak) vs. shoot through PBS and develop dose delivery algorithms for modeling biological effects for PBS-based FLASH proton therapy. These tools will be incorporated in the experimental plans of project 1-3. These Projects are supported by 4 Cores including an Administrative Core (Core A), Physics-Dosimetry Core (Core B), which will offer infrastructure services to harmonize dosimetry between various sites and a Comparative Pathology core (Core C) for tissue preparation for histopathological evaluation. Statistical services will be provided by Core D. Collectively, this highly integrated effort led by recognized leaders in Radiation and Tumor Biology, aims to define the biological, dosimetric and biophysical parameters and molecular mechanisms under which FLASH RT is most effective in tumors and tissues we deem the most likely to be first tested in clinical trials. It is our belief that only by acquiring this knowledge will this exciting and novel modality be ushered into the clinic in a safe and effective manner to improve therapeutic outcome and quality of life of cancer patients.