Mechanistic Insights into FLASH radiation for clinical use

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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.