Investigating the Effect of FLASH-Radiotherapy on Tumor and Normal Tissue

研究 FLASH 放射治疗对肿瘤和正常组织的影响

基本信息

批准号：
10650476
负责人：
Steven Jay Frank
金额：
$ 22.72万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650476
关键词：
Acute Address Affect Animal Cancer Model BALB/c Nude Mouse Biological Biological Models C3H/HeJ Mouse Cells Clinical Colitis Cystitis Dose Dose Rate Electrons Ensure External Beam Radiation Therapy Fibrosis Foundations Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Histology Human Image In Vitro Knowledge Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Modeling Modernization Motion Movement Mucositis Mus Normal tissue morphology Operative Surgical Procedures Organ Outcome PC3 cell line Pathologist Patient-Focused Outcomes Patients Pelvis Photons Physicians Positioning Attribute Prostate Prostate Adenocarcinoma Protons Qualifying Quality of life Radiation Radiation Dose Unit Radiation therapy Reproducibility Research Resources Roentgen Rays Scientist Site Systemic Therapy Taste Buds Testing Time Tissues Tongue Toxic effect Treatment Cost Treatment Efficacy Treatment Side Effects Treatment outcome Treatment-related toxicity Tumor Tissue Work Xenograft procedure anticancer treatment clinical effect conventional dosing cost effective therapy experience experimental study high reward high risk improved improved outcome in vivo in vivo Model individual patient irradiation millisecond mortality novel novel therapeutic intervention physical property pre-clinical preclinical study preservation prostate cancer model protective effect response sound tissue repair treatment duration tumor tumor xenograft

项目摘要

PROJECT SUMMARY Modern X-ray–based radiation therapy, delivered at conventional dose rates (~0.1 Gy/s, 2-Gy fractions, once daily) (C-XRT) has led to improved outcomes for patients with head & neck squamous cell carcinoma (HNSCC) and prostate cancer (PC). However, acute and long-term treatment-related side effects in both cancers have prompted the search for more biologically sound novel therapeutic strategies. Conventional dose rate proton radiotherapy (C-PT) may provide better tumor control with less treatment-related toxicity than C- XRT in both HNSCC and PC because of its biological enhancement effects and unique physical properties, but use of PT has been limited by its high cost. Here we aim to test the effects of a novel form of RT delivery, in which electrons, X-rays, or protons are delivered at ultra-high dose rates (≥40 Gy/s). This so-called “FLASH” RT can deliver curative doses to tumors within milliseconds, while simultaneously minimizing damage to surrounding tissues. The apparent protective effect of FLASH on normal tissues may further allow the use of very large fractions, which would both shorten overall treatment time and reduce costs, especially for PT. However, among the many unknowns at this time include (i) how FLASH-PT affects HNSCC and PC tumors and surrounding normal tissues, and (ii) whether FLASH-PT can reduce treatment toxicity while preserving treatment outcomes. We propose to address these important unknowns by testing the effects of FLASH-PT and C-PT in a unique model system, established by us, on tumor response and normal tissue damage in vivo. Our long-term objective is to establish a foundation for the clinical use of FLASH radiation to improve outcomes for patients with HNSCC or PC. In our preliminary work, we have generated a FLASH-PT experimental platform and homogenous dose distributions for FLASH-PT and C-PT for both in vitro and in vivo experiments. Our novel in vitro findings are that: (i) FLASH-PT kills more HN5 HNSCC cells than C-PT; and (ii) FLASH-PT preserves or enhances viability of Hs680.Tg normal tongue cells versus C-PT. Our immediate goals for this R21 are reflected in our specific aims: (1) Determine the functional and mechanistic effects of FLASH-PT vs C-PT in vivo in high-α/β tumor models (HNSCC); and (2) Determine the functional and mechanistic effects of FLASH-PT vs C-PT in vivo in low-α/β tumor models (PC). We expect that this high- risk/high-reward project will provide preclinical evidence regarding the in vivo effects of FLASH-PT vs C-PT (delivered in a variety of fraction numbers and sizes) on HNSCC and PC tumors and surrounding normal tissues. This knowledge will serve as the basis for choosing FLASH-PT or C-PT for individual patients, with the ultimate goals of improving treatment efficacy, minimizing treatment-related toxicity, and reducing treatment costs.

项目概要现代基于 X 射线的放射治疗，以常规剂量率（~0.1 Gy/s，2 Gy 分数，一次每日）（C-XRT）改善了头颈鳞状细胞癌患者的预后（HNSCC）和前列腺癌（PC）然而，两者都存在急性和长期治疗相关的副作用。癌症正在寻找生物学上更合理的新治疗策略。质子放疗（C-PT）可以提供更好的肿瘤控制，并且与 C-相比，治疗相关的毒性更少 XRT在HNSCC和PC中均因其生物增强作用和独特的物理特性而在HNSCC和PC中发挥作用，但 PT 的使用因其高成本而受到限制，我们的目标是测试一种新型 RT 递送形式的效果。以超高剂量率（≥40 Gy/s）发射电子、X 射线或质子，即所谓的“闪光”。放疗可以在几毫秒内向肿瘤提供治疗剂量，同时最大限度地减少对肿瘤的损害 FLASH 对正常组织的明显保护作用可能进一步允许使用非常大的分数，这既可以缩短总体治疗时间，又可以降低成本，特别是对于 PT。然而，目前的许多未知因素包括 (i) FLASH-PT 如何影响 HNSCC 和 PC 肿瘤和周围正常组织，以及 (ii) FLASH-PT 是否可以降低治疗毒性，同时保留我们建议通过测试 FLASH-PT 的效果来解决这些重要的未知因素。和 C-PT 在我们建立的独特模型系统中，关于体内肿瘤反应和正常组织损伤。我们的长期目标是为FLASH辐射的临床应用奠定基础，以改善在我们的前期工作中，我们生成了 FLASH-PT。体外和体内 FLASH-PT 和 C-PT 的实验平台和均匀剂量分布我们的新体外发现是：(i) FLASH-PT 比 C-PT 杀死更多的 HN5 HNSCC 细胞；与 C-PT 相比，FLASH-PT 可保留或增强 Hs680.Tg 正常舌细胞的活力。 R21 的目标反映在我们的具体目标中： (1) 确定高 α/β 肿瘤模型 (HNSCC) 体内 FLASH-PT 与 C-PT 的比较；以及 (2) 确定功能和 FLASH-PT 与 C-PT 在低 α/β 肿瘤模型 (PC) 中的体内机制效应风险/高回报项目将提供有关 FLASH-PT 与 C-PT 体内效果的临床前证据（以各种分数和大小提供）针对 HNSCC 和 PC 肿瘤以及周围正常组织这些知识将作为为个体患者选择 FLASH-PT 或 C-PT 的基础。最终目标是提高治疗效果、最大限度地减少治疗相关毒性和减少治疗成本。