Using experimentally-guided multi-scale modeling to determining the mechanism of FLASH tissue sparing

使用实验引导的多尺度建模来确定 FLASH 组织保留的机制

• 批准号: 10697374
• 负责人: Jan Patrick Oscar Schuemann
• 金额: $ 65.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697374
• 关键词: Animal Model; Biological Assay; Brain; Brain Glioblastoma; Breathing; Cells; Chemical Models; Chemicals; Chemistry; Clinic; Clinical; Clinical Trials; Collaborations; Complex; Cranial Irradiation; Cutaneous Lymphoma; DNA; DNA Damage; DNA Repair; Data; Daughter; Dose; Dose Rate; Electrons; Ensure; Fractionation; Human; Hydrogen Peroxide; In Vitro; Intestines; Iron; Kinetics; Lesion; Measures; Metastatic Neoplasm to the Bone; Metastatic malignant neoplasm to brain; Modeling; Mus; Normal tissue morphology; Outcome; Oxygen; Pathway interactions; Patient Recruitments; Patients; Phase; Physiologic pulse; Positron-Emission Tomography; Process; Production; Protons; Pulse Rates; Radiation induced damage; Radiation therapy; Radiochemistry; Reaction; Safety; Schedule; Skin; Structure; Sulfhydryl Compounds; Testing; Time; Tissue Therapy; Tissues; Translating; Translations; Tumor Tissue; Work; chemical kinetics; chemical reaction; conventional dosing; dosimetry; experimental study; improved; in vivo; irradiation; multi-scale modeling; pre-clinical; prevent; scale up; side effect; simulation; stem; tumor

Abstract FLASH irradiations, irradiations with dose rates >40 Gy/s, have been shown to greatly reduce radiation damage for normal tissue while not affecting tumor control. This sparing effect was demonstrated in multiple animal models, mostly using electron FLASH irradiations. The pre- clinical data generated a strong push to translate FLASH radiation therapy (RT) into the clinic. Only a few human patients have so far been treated with FLASH-RT. The first patient, a single cutaneous lymphoma lesion was treated with electron FLASH-RT. Recently, Varian an- nounced the first clinical trial of proton FLASH-RT (phase 1) and treated the first patients with symptomatic bone metastases. Yet many questions remain unanswered. Most significantly, the underlying mechanism of FLASH induced sparing of healthy tissue still remain elusive. As corollary, the constraints im- posed on the clinical parameters (e.g. dose, dose rate and time within and between treatment fields) to induce the FLASH tissue sparing effect are still not determined. While there are many experimental efforts currently being pursued, my team has worked on understanding FLASH both from an experimental as well as theoretical point of view. Our ex- perimental preliminary data show proton FLASH tissue sparing in intestine, brain and skin. Our theoretical preliminary data include modeling oxygen depletion and simulations of radi- ochemistry using TOPAS-nBio, a mechanistic Monte Carlo framework developed by our group. Our central hypothesis is that the FLASH effect is caused by a combination of (stem) cells in a low-oxygen niche and long-lived (µs to ms) daughter products of chemical reactions involving oxygen. We propose an interplay between experiments and modeling to determine the under- lying mechanism of FLASH-RT tissue sparing by employing TOPAS-nBio to investigate the involved chemical reactions based on their intrinsic time features. We propose to test the hypothesis and validate the model with the following aims: SA 1: Investigate the mechanisms of proton FLASH-RT 1. Conduct multi-scale experiments to guide the modeling efforts. 2. Model the mechanism and chemical processes at relevant time scales in TOPAS-nBio. SA 2: Validate the model and determine clinical parameters for FLASH tissue sparing.

抽象的 FLASH 照射（剂量率 >40 Gy/s 的照射）已被证明可以大大减少 放射线对正常组织造成损伤，同时不影响肿瘤控制。这种节约效应是 在多种动物模型中得到证实，主要使用电子闪光照射。预 临床数据有力地推动了将 FLASH 放射治疗 (RT) 转化为临床。 迄今为止，只有少数人类患者接受了 FLASH-RT 治疗。第一个病人是一位 采用电子FLASH-RT治疗单皮肤淋巴瘤病灶。最近，瓦里安- 宣布首次质子 FLASH-RT 临床试验（一期）并治疗第一批患者 有症状的骨转移。 然而，许多问题仍未得到解答。最重要的是，其基本机制 FLASH 诱导的健康组织保护仍然难以捉摸。作为推论，约束条件是 根据临床参数（例如剂量、剂量率以及治疗期间和治疗之间的时间） 场）诱导 FLASH 组织保护效果尚未确定。 虽然目前正在进行许多实验工作，但我的团队已经致力于 从实验和理论的角度理解 FLASH。我们的前任 实验初步数据显示质子FLASH组织在肠道、大脑和皮肤中保留。 我们的理论初步数据包括氧气消耗建模和辐射模拟 使用我们小组开发的机械蒙特卡罗框架 TOPAS-nBio 进行化学分析。 我们的中心假设是，FLASH 效应是由（干）细胞的组合引起的 低氧生态位和长寿命（μs 至 ms）的化学反应子产物，涉及 氧。我们提出实验和建模之间的相互作用来确定欠缺 通过使用 TOPAS-nBio 来研究 FLASH-RT 组织保护的潜在机制 涉及基于其固有时间特征的化学反应。 我们建议通过以下目标来检验假设并验证模型： SA 1：研究质子 FLASH-RT 的机制 1. 进行多尺度实验来指导建模工作。 2. 在 TOPAS-nBio 中对相关时间尺度的机制和化学过程进行建模。 SA 2：验证模型并确定 FLASH 组织保留的临床参数。

项目成果

Absence of Tissue-Sparing Effects in Partial Proton FLASH Irradiation in Murine Intestine.

• DOI: 10.3390/cancers15082269
• 发表时间: 2023-04-13
• 期刊: Cancers
• 影响因子: 5.2

Proton FLASH effects on mouse skin at different oxygen tensions.

质子闪光在不同氧张力下对小鼠皮肤的影响。

• DOI: 10.1088/1361-6560/acb888
• 发表时间: 2023
• 期刊: Physics in medicine and biology
• 影响因子: 3.5
• 作者: Zhang,Qixian;Gerweck,LeoE;Cascio,Ethan;Yang,Qingyuan;Huang,Peigen;Niemierko,Andrzej;Bertolet,Alejandro;Nesteruk,KonradPawel;McNamara,Aimee;Schuemann,Jan
• 通讯作者: Schuemann,Jan