Translational Studies in FLASH Particle Radiotherapy

FLASH粒子放射治疗的转化研究

基本信息

批准号：
10573278
负责人：
Constantinos Koumenis
金额：
$ 239.13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573278
关键词：
Address Adverse event Affect Algorithms Animals Annual Reports Attention Belief Biological Biological Models Biometry Blood Vessels Bone structure Cancer Patient Canis familiaris Carbon Carbon ion Cells Chest Clinic Clinical Clinical Trials Collaborations Comparative Pathology Development Dose Dose Rate Electrons Ensure Esophagus Evaluation Fibrosis Genetic Genetic Determinism Goals Growth Heart Human Hypoxia Image Analysis Immunofluorescence Immunologic Inflammation Infrastructure Injury International Intestines Knowledge Knowledge acquisition Lead Lung Lymphedema Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Methodology Modality Modeling Molecular Monitor Mus Nature Non-Small-Cell Lung Carcinoma Normal tissue morphology Operative Surgical Procedures Oxygen Patients Phase Phase I/II Trial Physics Pre-Clinical Model Procedures Protons Quality of life Radiation Radiation Dose Unit Radiation Toxicity Radiation therapy Radiation-Induced Cancer Radiobiology Reporting Research Research Design Resources Sample Size Scanning Scheme Schools Second Primary Neoplasms Services Site Speed Stains System TP53 gene Techniques Technology Testing Therapeutic Time Tissues Toxic effect Transgenic Mice Trichrome stain method Tumor Biology Universities Validation Variant antitumor effect barrier to care beam dynamics beamline biophysical properties cancer cell comparative efficacy dosimetry immune cell infiltrate improved irradiation lung injury meetings mouse model novel operation osteosarcoma particle particle therapy preclinical study programs proton therapy quality assurance quantitative imaging radiation mitigation response sarcoma spatiotemporal statistical service stem cell population success symposium systems research therapy outcome tissue injury tissue preparation tool transcriptomics translational study treatment planning tumor tumor growth

项目摘要

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.

项目概要放射治疗 (RT) 用于治疗许多癌症，包括肉瘤和肺癌胰腺癌。尽管过去几十年取得了显着的进步，但仍有很大的空间由于患者仍然出现放疗引起的损伤或继发性恶性肿瘤，因此情况有所改善。闪光放射治疗，以超高剂量率提供大剂量辐射可能会降低毒性。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，而两种方式在控制恶性生长方面是等效的。项目 1 重点关注胰腺癌，将定义剂量测定和生物物理参数，使用 FLASH 质子治疗 (F-PRT) 可以最大程度地保护正常肠道组织，而不会造成任何影响抗肿瘤作用。它将通过以下方式描述正常肠道组织差异反应的机制方面：重点关注干细胞/祖细胞群的相对保留。项目1还将采用p53+/-转基因小鼠模型剖析标准质子治疗 (S-PRT) 不同胃肠道毒性的遗传决定因素与 F-PRT 相比。项目 2 将探索 F-PRT 改善不良事件（炎症、纤维化、淋巴水肿、骨骼结构变化、辐射诱发的癌症），这些都对治疗造成障碍 RT 肉瘤。我们还将开展一项 1/2 期试验，治疗患有骨肉瘤的犬类患者最终使用 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。研究将集中于正常组织的缓解 NSCLC 损伤，重点关注正常组织和瘤内缺氧对以下反应的影响 C-RT。最后，项目 4 将开发并验证笔形束扫描 (PBS) 技术在粒子 F-RT。它将通过 PBS 和拍摄来分析时空变化和 SOBP（扩展布拉格峰）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。这些工具将纳入项目1-3的实验计划中。这些项目由 4 个核心支持包括管理核心（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站点之间的剂量测定和组织比较病理学核心（核心 C）的服务为组织病理学评估做准备。统计服务将由Core 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综合的努力，旨在定义 FLASH 的生物学、剂量学和生物物理参数以及分子机制放疗对于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最有效。这是我们的相信只有获得这些知识，这种令人兴奋和新颖的模式才能被引入以安全有效的方式进行临床，以改善癌症患者的治疗结果和生活质量。