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

• 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
• 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

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.

项目总结 现代基于X射线的放射治疗，按常规剂量率(~0.1Gy/S，2Gy次，一次 (C-XRT)可改善头颈部鳞状细胞癌患者的预后 (HNSCC)和前列腺癌(PC)。然而，急性和长期治疗相关的副作用在两者中 癌症促使人们寻找更具生物学意义的新治疗策略。常规剂量 率质子放射治疗(C-PT)可能比C-PT提供更好的肿瘤控制，且与治疗相关的毒性更小。 由于其生物增强效应和独特的物理性质，XRT在HNSCC和PC中都有应用，但 PT的使用因其高昂的成本而受到限制。在这里，我们旨在测试一种新的RT交付形式的效果，在 这些电子、X射线或质子以超高的剂量率传输(≥40GY/S)。这个所谓的“闪光” RT可以在毫秒内为肿瘤提供治疗剂量，同时将对 周围的组织。闪光对正常组织的明显保护作用可能进一步允许使用 非常大的组分，这将缩短整体治疗时间并降低成本，特别是对PT。 然而，在目前的许多未知因素中，包括：(I)Flash-PT如何影响HNSCC和PC肿瘤 以及(Ii)Flash-PT能否在保存的同时减少治疗毒性 治疗结果。我们建议通过测试Flash-PT的效果来解决这些重要的未知问题 和C-PT在体内对肿瘤反应和正常组织损伤的独特模型系统。 我们的长期目标是为闪光辐射的临床应用奠定基础，以提高 HNSCC或PC患者的预后。在我们的前期工作中，我们已经生成了一个闪存PT Flash-PT和C-PT的体内外实验平台和均匀剂量分布 实验。我们的新的体外发现是：(I)Flash-PT比C-PT对HN5 HNSCC细胞的杀伤更多；以及(Ii) 与C-PT相比，Flash-PT保存或提高了Hs680正常舌细胞的活性。我们的直接客户 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；(2)测定 低α/β肿瘤模型(PC)中Flash-PT与C-PT的体内机制比较我们预计这个高度- 风险/高回报项目将提供有关Flash-PT与C-PT体内效应的临床前证据 (以不同的分数和大小提供)用于HNSCC和PC肿瘤及其周围正常 纸巾。这些知识将作为为个别患者选择闪光PT或C-PT的基础， 提高治疗效果、最大限度减少与治疗相关的毒性和减少治疗的最终目标 成本。