New insights into the cellular response to complex DNA damage induced by proton beam therapy

放射治疗仍然是许多人类癌症最有效的治疗方法，英国质子束治疗（PBT）设施的出现，特别是在曼彻斯特和伦敦（分别从2018年底和2021年开始运营），可能标志着癌症治疗的新时代。这是因为PBT是一种精确的技术，能够将大部分辐射剂量直接输送到癌症，从而使周围正常组织免受任何不必要的辐射剂量，并减少常规放射治疗中常见的不良副作用。然而，尽管已知包括PBT在内的放射疗法通过对癌细胞的DNA造成损伤而导致癌细胞死亡，对于细胞修复某些类型的DNA损伤的机制仍然没有完全的了解，并且可能导致对治疗的显着抵抗。因此，该提案旨在揭示癌细胞修复DNA损伤的基本生物学机制的新知识。PBT，未来的目标是为开发与PBT相结合的新策略提供线索，以有效治疗癌症。事实上，这项研究将主要采用来自头颈癌患者的细胞，由于当地发病率高，头颈癌是利物浦大学的优先肿瘤研究领域，但也是一种越来越多地用PBT治疗的肿瘤。因此，该提案具有设计未来使用PBT治疗头颈癌患者的最佳治疗的巨大潜力，从而减少不良副作用并改善生活质量，但更重要的是提高总生存率。

Radiotherapy is still the most effective treatment for a number of human cancers, and the emergence of proton beam therapy (PBT) facilities in the UK, particularly in Manchester and London (operational from late 2018 and 2021, respectively), is likely to signal a new era for cancer treatment. This is due to the fact that PBT is a precision technique able to deliver the majority of the radiation dose directly to the cancer, thus sparing the surrounding normal tissues of any unwanted dose of radiation and reducing the adverse side-effects that are commonly observed with conventional radiotherapy. However whilst radiotherapy, including PBT, is known to act by causing damage to the DNA of cancer cells causing them to die, there is still not a complete understanding of the mechanisms which the cells use to repair certain types of DNA damage and that can cause significant resistance to treatment.This proposal therefore aims to reveal new knowledge into the basic biological mechanisms that cancer cells use to repair DNA damage caused by PBT, with the future goal of providing leads to the development of new strategies in combination with PBT for effective cancer treatment. Indeed, this study will largely employ cells derived from patients with head and neck cancer, which is a priority tumour research area within the University of Liverpool due to the high local incidence, but also a tumour which is increasingly being treated with PBT worldwide. Therefore, this proposal has the significant potential to devise future optimal treatments using PBT for head and neck cancer patients, leading to reductions in adverse side-effects and improvement in quality of life, but more importantly to increases in overall survival rates.