Translational Studies in FLASH Particle Radiotherapy

项目总结 放射治疗(RT)被用于许多癌症的治疗，包括肉瘤和肺癌以及 胰腺癌。尽管在过去的几十年里取得了显著的进步，但仍有很大的空间 随着患者仍在发生放射治疗引起的损伤或第二次恶性肿瘤，情况有所改善。闪光放射治疗， 它以超高的剂量率提供大剂量的辐射，可能会降低毒性。我们的整体 假设质子/碳粒子闪光RT在保护方面优于标准粒子RT 而这两种方法在控制恶性生长方面将是同等的。 项目1，重点是胰腺癌，将定义剂量学和生物物理参数，以 将使用闪光质子疗法(F-PRT)最大限度地保留正常肠道组织而不会影响 抗肿瘤作用。它将描绘正常肠道组织差异反应的机制方面，通过 重点放在干细胞/祖细胞群体的相对节省上。项目1还将采用P53/-转基因 标准质子疗法不同胃肠道毒性遗传决定因素的小鼠模型研究 VS F-PRT。项目2将探索F-PRT缓解不良事件(炎症、纤维化、 淋巴水肿、骨骼结构改变、辐射诱发癌症)，这些都对治疗构成了障碍 肉瘤伴RT。我们还将进行一项1/2期试验，治疗患有骨肉瘤的犬类患者。 与F-PRT完全一致。项目3将比较闪光放疗和碳离子放射治疗(C-RT)的疗效。 RT)与标准剂量率进行比较，并与电子F-RT进行比较。研究将集中在对正常组织的缓解上 非小细胞肺癌的损伤，重点是正常组织和肿瘤内缺氧对术后反应的影响 C-RT。最后，项目4将开发和验证铅笔束扫描(PBS)技术在粒子中的使用 F-RT。它将通过PBS和PBS分析时空变化和SOBP(扩散布拉格峰)与拍摄 开发剂量传递算法以模拟基于PbS的闪光质子治疗的生物效应。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 包括一个行政核心(核心A)、物理剂量测定核心(核心B)，它将提供基础设施 协调不同部位和组织的比较病理学核心(核心C)之间的剂量测定服务 为组织病理学评估做准备。统计服务将由核心D提供。 总的来说，这项由放射和肿瘤生物学领域公认的领导者领导的高度整合的努力旨在 定义闪光的生物学、剂量学和生物物理参数和分子机制 RT对我们认为最有可能在临床试验中首先测试的肿瘤和组织最有效。这是我们的 相信只有通过获得这种知识，这种令人兴奋和新颖的方式才会被带入 以安全有效的方式进行临床治疗，以提高癌症患者的治疗结果和生活质量。

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.