Project 1: Optimizing Treatment of GBM by FLASH

项目概要/摘要-项目1：通过FLASH优化GBM治疗 我们建议创建一个研究项目，题为“提高脑肿瘤的治疗指数 通过创新的FLASH放射治疗（FLASH-RT），“专注于将一种新的放射疗法 快速进入临床。有待检验的总体假设是，超高剂量的辐射 剂量率（与当前临床实践中使用的低得多的剂量率相比）可以显著改善 正常的组织并发症，同时保持可接受的，如果没有改善的肿瘤控制。为了验证这个假设， 该计划将部署一系列全面的临床前研究，将严格评估肿瘤控制， FLASH-RT和常规剂量后的神经认知结局和由此产生的脑辐射损伤 速率辐照总的来说，这些研究将产生快速翻译所需的必要数据集。 新型FLASH照射平台的临床应用。小鼠临床前研究，评估原位 肿瘤控制、认知、神经元和血管结构、免疫调节和氧依赖性 辐射损伤的机制与GBM狗患者的临床试验相结合，以告知肿瘤学家 这种潜在的范式转变方法的潜在好处。该项目的目标将 由剂量测定/物理学/建模核心和神经行为核心进行的活动促进。 项目1将侧重于评估治疗指标，包括肿瘤控制和正常脑损伤， FLASH-RT与常规剂量率照射的比较。原位荷瘤小鼠将用 临床相关场景下的FLASH和常规RT：单次分割和分割，有和无 同步化疗，使用电子和MV X射线束。实验将在我们的 这些机构（CHUV、斯坦福大学和印第安纳州大学）使用我们的新型FLASH辐照平台， 核心2和3。我们将评估FLASH差异效应的细胞和分子机制 通过评估神经元和肿瘤结构以及炎症/免疫调节的标志物。 这项创新计划项目赠款的成功得到了无与伦比的广度和深度的支持， 我们在加州大学欧文分校、斯坦福大学、SLAC国家加速器的多学科调查团队 实验室、CHUV/洛桑大学医院和开创了这一领域的印第安纳州大学 开发了进行FLASH-RT研究的初始实验基础设施，并产生了强大的 增加治疗指数的临床前证据，包括放射肿瘤学，放射生物学， 医学物理学、临床前成像和加速器科学。 总之，项目1将通过系统测试为FLASH-RT的近期临床转化铺平道路 FLASH和常规剂量率照射的临床相关方案，并将补充研究 项目2-4侧重于长期的神经毒性，扩展到其他物种的临床前和物理化学 FLASH-RT机制。

PROJECT SUMMARY/ABSTRACT – Project 1: Optimizing Treatment of GBM by FLASH We are proposing the creation of a research program entitled, “Increasing the therapeutic index of brain tumor treatment through innovative FLASH radiotherapy (FLASH-RT),” focused on translating a novel irradiation modality rapidly into the clinic. The overall hypothesis to be tested is that radiation delivered at ultra-high dose rates (compared to the much lower dose rates used in current clinical practice) can significantly ameliorate normal tissue complications while maintaining acceptable if not improved tumor control. To test this hypothesis, the program will deploy a comprehensive series of preclinical studies that will critically evaluate tumor control, neurocognitive outcomes and resultant radiation injury to the brain following FLASH-RT and conventional dose rate irradiation. Collectively, these studies will generate the requisite data sets required for the rapid translation of the novel FLASH irradiation platform to the clinical setting. Preclinical studies in mice assessing orthotopic tumor control, cognition, neuronal and vascular structure, immunomodulation, and oxygen-dependent mechanisms of radiation injury are coupled with a clinical trial in GBM dog patients to inform the oncologists of the potential benefits of this potentially paradigm shifting approach. The objectives of this program project will be facilitated by the activities conducted by the Dosimetry/Physics/Modeling core and the Neurobehavioral core. Project 1 will focus on the assessing the therapeutic index, comprising tumor control and normal brain injury, of FLASH-RT compared to conventional dose rate irradiation. Orthotopic tumor-bearing mice will be treated with FLASH and conventional RT under clinically relevant scenarios: single fraction and fractionated, with and without concurrent chemotherapy, using electron and MV x-ray beams. The experiments will be conducted across our institutions (CHUV, Stanford, and Indiana University) using our novel FLASH irradiation platforms, supported by Cores 2 and 3. We will evaluate cellular and molecular mechanisms underlying the differential effects of FLASH by assessing neuronal and tumor structure, and markers of inflammation/immunomodulation. The success of this innovative program project grant is bolstered by the unparalleled breadth and depth of our multi-disciplinary investigative team at UC Irvine, Stanford University, SLAC National Accelerator Laboratory, CHUV/Lausanne University Hospital, and Indiana University that has pioneered the development of the initial experimental infrastructure for conducting FLASH-RT research and produced strong preclinical evidence of increased therapeutic index, comprising expertise in radiation oncology, radiobiology, medical physics, and preclinical imaging and accelerator science. In summary, Project 1 will pave the way for near-term clinical translation of FLASH-RT by systematically testing FLASH and conventional dose-rate irradiation under clinically relevant regimens, and will complement studies in Projects 2-4 focused on longer-term neurotoxicity, expanding to other species preclinically, and physico-chemical mechanisms of FLASH-RT.