Establishing a UK National Preclinical Photon-FLASH Radiotherapy Facility (FLASH-SARRP)

Radiotherapy treats cancers through the precise delivery of high doses of radiation to tumours, killing cancerous cells by damaging their DNA. While radiation can be precisely targeted to tumours, some normal tissue is also necessarily exposed to radiation, and avoiding excessive damage to normal tissue is a major limitation in the treatment of many cancers.

Currently, most radiotherapy is delivered using X-rays (photons) with individual treatments delivered over a period of minutes. However, recent evidence has suggested that delivering radiotherapy much more rapidly - with treatment times of less than a second - significantly reduces the damage radiation causes to normal tissue while retaining its efficacy against tumours. This has been dubbed the "FLASH effect", and has the potential to significantly improve the flexibility and efficacy of radiotherapy.

This effect has been unexpected, given established knowledge of how tumours respond to radiotherapy, and as a result is the subject of a significant amount of research. However, most of this research has been carried out using custom-designed radiation sources which expose cells to electrons, rather than photons as used in most clinical practice. Due to the novel nature of the FLASH effect, it is currently unknown if these different types of radiation interact with the FLASH effect in different ways, and how current information on the FLASH effect may be related to clinical practice.

This proposal seeks to provide funding for a first preclinical photon FLASH-SARRP (Small Animal Radiotherapy Research Platform). This would offer a unique resource, able to reproduce FLASH dose rates using photons in small animal models of cancer. This would enable the detailed exploration of the mechanisms of FLASH in the same modality as is used clinically, providing a unique insight into its underlying mechanisms and a valuable complement to existing resources within the UK.

We will use this source to validate the FLASH effect in photon exposures, and then explore its mechanistic basis, based on physical, chemical and biological effects within tumours and normal tissues. This work will be intergated into our established radiation biology research portfolio, and used to support the translation of FLASH into an effective clinical tool for the treatment of cancer.

Recent observations of the 'FLASH effect' suggest that exposing animals to radiation at high dose rates (>40 Gray/second) causes significantly less damage to normal tissues than a similar dose delivered at conventional (~Gray/minute) dose rates, while preserving tumour efficacy. This has the potential to significantly improve the therapeutic window in radiation therapy and improve outcomes. However, it remains poorly understood, with no consensus on the underlying mechanisms driving this effect.

A large amount of research is currently ongoing on the FLASH effect to attempt to quantify its effects and understand the underlying mechanisms. However, most of this research is currently carried out with either electrons or protons, despite the vast majority of clinical treatments being delivered with photons.

This proposal seeks to help bridge this gap by supporting the purchase of a FLASH-SARRP (Small Animal Radiotherapy Research Platform). This first-of-its-kind dedicated preclinical research platform offers FLASH dose rates (>100 Gray/second) coupled with advanced preclinical CT imaging enabling robust treatment planning and delivery. This would enable the validation and characterisation of the FLASH effect with a radiation modality much more closely matching clinical practice, potentially accelerating its translation as a clinical tool. This will also enable us to investigate the interaction of FLASH effects with other ongoing research, including prediction of intrinsic radiosensitivity, radiosensitiser development, and effects of spatial modulation of treatment.

This resource would integrate effectively with our existing infrastructure and expertise in small animal radiotherapy research and FLASH effects. It will also be made available as a research platform for other users, to foster a collaborative network across the UK and support links with other FLASH research modalities such as protons and electrons at other institutes.