Mechanistic Insights into FLASH radiation for clinical use

该计划将研究支持FLASH在正常组织中观察到的高度有益的保护作用的生物学机制，以及是否可以通过改变物理FLASH光束特性或将其与潜在的小分子反应调节剂结合来进一步提高治疗率。从这项拟议的研究中获得的知识将有助于将FLASH放射治疗（RT）转化为临床实践。从机制上讲，氧和自由基-自由基相互作用的作用，DNA损伤反应的诱导，以及炎症和免疫反应将被追求，以了解FLASH辐射如何增加正常组织和肿瘤之间的RT治疗指数。在技术方面，该项目将定义可应用于临床的最佳FLASH光束特性。这些研究的结果应该对英国的FLASH开发产生很大的影响，这可能使所有未来接受RT作为癌症治疗一部分的患者受益。该方案的目标是：（1）确定负责通过FLASH辐射选择性地保留正常组织而不是肿瘤组织的生物学机制，即所谓的FLASH效应。这个目标将探讨正常组织和肿瘤之间的差异，在氧消耗，自由基-自由基相互作用，DNA损伤反应和炎症反应的作用。第二个目标（2）是识别最佳的物理闪光光束特性以使闪光效应最大化。我们将调制的剂量，分馏方案，时间脉冲结构的光束传输，比较不同粒子的光束和不同的线性能量转移（LET）。此外，我们将修改我们目前的临床前电子直线加速器，以允许光子闪光照射，未来的闪光提供直线加速器为基础的放射治疗。我们的最终目标（3）将集中在如何将FLASH转化为临床研究，使用电子束治疗浅表靶点，使用质子束治疗深层靶点。在准备临床研究时，我们将评估质子FLASH治疗的不同治疗计划策略，开发FLASH剂量测定解决方案并进行安全性研究。此外，我们将设计早期临床FLASH研究，重点关注安全性和可行性，但这些研究还将包括正常组织毒性和肿瘤缓解数据的评价。

This programme will investigate the biological mechanisms that underpin the observed and highly beneficial sparing effect of FLASH in normal tissues as well as whether the therapeutic ratio can be further enhanced by altering the physical FLASH beam characteristics or combining it with potential small molecule response modifiers. The knowledge to be gained from this proposed research will help translate FLASH radiotherapy (RT) into clinical practice. Mechanistically, the role of oxygen and radical-radical interaction, the induction of DNA damage response, and the inflammatory and immune response will be pursued to understand how FLASH radiation increases the therapeutic index of RT between normal tissue and tumour. On the technical side, this project will define optimal FLASH beam characteristics that can be applied in the clinic. The results of these studies should have a high impact on FLASH development in the UK that can potentially benefit all future patients receiving RT as part of their cancer treatment. The programme aims are: (1) to identify the biological mechanisms responsible for the selective sparing of normal tissue and not tumour tissues by FLASH radiation, the so-called FLASH effect. This aim will explore the differences between normal tissues and tumours in regards to the role of oxygen consumption, radical-radical interactions, the DNA damage response and inflammatory responses. The second aim (2) is to identify optimal physical FLASH beam characteristics to maximise the FLASH effect. We will modulate the dose, fractionation scheme, temporal pulse-structure of the beam delivery, compare beams of different particles and of different LET (Linear Energy Transfer). Additionally, we will modify our current preclinical electron linac to allow for photon FLASH irradiation, the future of FLASH delivered by linac-based radiotherapy. Our final aim (3) will be focused on how to translate FLASH into clinical studies, using electron beams for superficial targets, and using proton beams for deep-seated targets. In preparation for clinical studies, we will evaluate different treatment planning strategies for proton FLASH treatments, develop FLASH dosimetry solutions and perform safety studies. Additionally, we will design early clinical FLASH studies with a focus on safety and feasibility, but these will also include evaluation of normal tissue toxicity and tumour response data.