Exploiting the radiobiological potential of protons and high-LET radiation

The strategic focus of the proposed Birmingham RadNet Centre (BRNC) is to explore the radiobiological impact of protons and high linear energy transfer (LET) radiation at the molecular and cellular level, and to perform translational research to exploit these radiation types for optimising the treatment of specific cancers (Figure 1).

This programme will be delivered using our unique, and national, radiation resources for proton, helium ion and boron neutron capture therapy (BNCT) irradiations.

The BRNC will enhance natural synergies and existing scientific expertise in radiation biology and DNA replication, stability and repair, but also tumour hypoxia and metabolism.

Clinical strengths in head and neck cancers, brain and paediatric cancers will further synergise with biological research in order to inform on strategies using protons and high-LET radiation for optimal tumour radiosensitisation whilst minimising the impact on the normal tissues and organs at risk.

Our long-term goal is to contribute significantly to improvements in patient outcome and reduced treatment toxicities following radiotherapy.

Collectively our multidisciplinary expertise in radiation biology, physics and oncology has the potential to be transformative for cancer patients.

Our vision for the BRNC is focussed on the successful delivery of two synergistic themes, and which importantly will build on our current core strengths;- • Radiobiological effects of protons and high-LET radiation at conventional and ultra-high (FLASH) dose rates.

We will expand on our ongoing preclinical research to provide a further understanding of the underpinning biological effects of protons, helium ions and BNCT, ranging from ~1 keV/µm to >100 keV/µm, on normal and tumour cell models.

The effects of FLASH and spatial fraction of dose (minibeams), through which significant normal tissue sparing has been shown, will also be investigated.

A major focus will be on analysis of the extent and nature of DNA damage, temporal analysis of DNA damage repair and replication, metabolomic analysis, as well as the influence of tumour hypoxia on these processes. • Translational radiobiology research using protons and high-LET radiation.

We will focus on utilising and expanding upon our established models of head and neck cancers, adult brain (glioblastoma) and paediatrics (rhabdomyosarcoma) in translational research using protons, helium ions and BNCT.

Here, we will use a broad range of experimental models, but with a particular focus on patient-derived organoids, organotypic raft cultures and a chick embryo model, to examine the tumour response to the different types of radiation.

Additionally, we will explore and identify specific inhibitor-radiation combinations leading to optimal tumour radiosensitisation.

To enable our vision, we will use our existing infrastructure as well as strategic posts provided through the BRNC, to enhance our capacity for radiobiology research focussed on protons and high-LET radiation.

This has high translational potential for the benefit of cancer patients, particularly those of the head and neck, adult brain and paediatrics.

Identification of optimal radiosensitisation strategies from these preclinical studies will inform the design of future clinical trials using these precision-targeted radiotherapy techniques.