FLASH radiotherapy delivers a full course of radiation in a fraction of a second, and this programme will work out exactly why it spares healthy tissue while still destroying tumours. Standard radiotherapy damages healthy tissue around a tumour, limiting how much radiation can be given safely. FLASH—ultra-high dose rate radiation—dramatically reduces that collateral damage in animal studies, but no one knows why. Without that mechanistic understanding, clinicians cannot reliably design FLASH treatments for patients. This programme will pin down the biological mechanisms: how oxygen consumption, radical chemistry, DNA damage responses, and inflammation differ between normal and tumour tissues after FLASH versus conventional radiation. If the mechanisms are identified, FLASH could transform radiotherapy. Patients might receive higher, more effective tumour doses with fewer side effects—less fatigue, less damage to skin, gut, and lungs. The programme will also define the optimal beam characteristics (dose, pulse structure, particle type) and develop clinical protocols for electron FLASH (superficial tumours) and proton FLASH (deep-seated tumours). Early safety and feasibility studies are built into the plan. The work is directly translational: it aims to move FLASH from preclinical labs into UK clinical trials within the grant period.
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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.
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