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：
10333797
负责人：
Constantinos Koumenis
金额：
$ 247.85万
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/10333797
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 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 I/II Trial Physics Population 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 Tumor Tissue Tumor-infiltrating immune cells Universities Validation Variant antitumor effect barrier to care base beamline biophysical properties cancer cell comparative efficacy dosimetry improved irradiation lung injury meetings mouse model novel operation osteosarcoma particle particle therapy preclinical study proton therapy quality assurance quantitative imaging radiation mitigation response sarcoma spatiotemporal statistical service stem stem cells success symposium systems research therapy outcome tissue injury tissue preparation tool transcriptomics translational study treatment planning tumor tumor growth

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 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 I/II Trial Physics Population 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 Tumor Tissue Tumor-infiltrating immune cells Universities Validation Variant antitumor effect barrier to care base beamline biophysical properties cancer cell comparative efficacy dosimetry improved irradiation lung injury meetings mouse model novel operation osteosarcoma particle particle therapy preclinical study proton therapy quality assurance quantitative imaging radiation mitigation response sarcoma spatiotemporal statistical service stem stem cells success symposium systems research therapy outcome tissue injury tissue preparation tool transcriptomics translational study treatment planning tumor tumor growth

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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.

项目摘要放射疗法（RT）用于许多癌症，包括肉瘤和肺和胰腺癌。尽管在过去的几十年中有了显着改善，但仍然有很多空间随着患者仍会出现RT诱发的损伤或第二次恶性肿瘤的改善。闪光放射疗法，以超高剂量速率提供大剂量的辐射可能会降低毒性。我们的整体假设是质子/碳颗粒闪光RT在保护方面优于标准粒子RT 正常组织虽然两种方式将在控制恶性生长方面有计划。侧重于胰腺癌的项目1将定义剂量学和生物物理参数最大程度地利用闪光质子疗法（F-PRT）来最大程度地避免正常的肠组织抗肿瘤效应。它将通过专注于茎/祖细胞群的相对较高。项目1还将采用P53 +/-转基因小鼠模型剖析标准质子疗法差异GI毒性的遗传决定因素（S-PRT） vs f-prt。项目2将探讨F-PRT改善不良事件的能力（炎症，纤维化，淋巴水肿，骨骼结构的变化，辐射引起的癌症）构成了治疗的障碍肉瘤与rt。我们还将进行1/2期试验，该试验将治疗骨肉瘤的犬类患者与F-PRT一起确定。项目3将比较给出的闪光灯与碳离子放射疗法的功效（C- RT）与标准剂量率，并将其与电子F-RT进行比较。研究将集中于缓解正常组织 NSCLC的损伤，重点是正常组织和肿瘤内缺氧对反应的影响 C-RT。最后，项目4将开发和验证铅笔梁扫描（PBS）技术的粒子技术 F-RT。它将分析时空变化和SOBP（散布布拉格峰）与PBS射击和开发剂量输送算法，以建模基于PBS的闪光质子疗法的生物学效应。这些工具将纳入项目1-3的实验计划中。这些项目得到4个核心的支持包括行政核心（核心A），物理限制核心（核心B），该核心将提供基础架构提供统一各个站点和组织比较病理核心（核心C）之间的剂量测定的服务准备组织病理学评估。统计服务将由CoreD提供。总体而言，这项由公认的辐射和肿瘤生物学领导者领导的高度综合努力的目标定义生物学，剂量学和生物物理参数以及分子机制 RT在肿瘤和组织中最有效，我们认为最有可能在临床试验中进行测试。这是我们的相信只有获取这些知识才能将这种令人兴奋和新颖的方式带入诊所以安全有效的方式改善癌症患者的治疗结果和生活质量。