INVESTIGATING THE RADIOBIOLOGY OF PROTONS AND HIGH-LET RADIATION; DISCOVERING TARGETS TO OPTIMISE TUMOUR RADIOSENSITIVITY

<b>Background and Aims: </b>Particle ion therapy is increasingly being utilised as a precision targeted approach for cancer treatment, whilst taking advantage of the enhancement in biological effectiveness due to increases in linear energy transfer (LET). These include protons which are relatively low-LET, compared to helium ions and boron neutron capture therapy (BNCT) that are relatively high-LET. Densely ionising particles lead to the formation of complex DNA damage (CDD), where several lesions are induced in close proximity within DNA, which ultimately drives tumour cell killing. However, further research is needed to fully understand the biological response to CDD as a function of LET, and to devise strategies leading to combinatorial therapies that can optimise cancer treatment in the clinic.<br/><br/><b>Methods: </b>At the University of Birmingham, and as part of the Cancer Research UK RadNet Birmingham Centre, we have unique resources for delivering protons, helium ions and BNCT to cell based models via the MC-40 cyclotron and high-flux accelerator-driven neutron source. With a specific focus on head and neck squamous cell carcinoma, we have analysed the impact of the different radiotherapy types on survival/viability of 2D cell lines and 3D patient-derived organoids, correlated with levels and repair of DNA single and double strand breaks, plus CDD. siRNA knockdowns and inhibitors have been used to target specific proteins in combination with the radiation types.<br/><br/><b>Results:</b> We have demonstrated the ability of relatively high-LET protons generated at the Bragg peak to induce significant decreases in tumour cell survival post-irradiation through elevated levels of CDD, versus low-LET protons and X-rays. We have further identified key DNA repair proteins including PARP-1, PARG and OGG1 that are essential for CDD repair, and whose inhibition with targeted drugs can further enhance the biological effectiveness of high-LET protons. Work is currently underway to determine the comparative impact of high-LET helium ions and BNCT (using boric acid and boronophenylalanine) with/without inhibitors on the biological response, compared to protons and X-rays.<br/><br/><b>Conclusions:</b> Our goal is to enhance our understanding of the radiobiology of protons and high-LET radiation, and which can be used as a basis for decision-making in the personalised treatment of head and neck cancer patients.