Novel strategies for radioresistant head and neck cancers through targeting the DNA damage response in combination with high-precision proton beam the

质子束治疗（PBT）在世界范围内越来越多地用于治疗特定的癌症，如头颈部鳞状癌（HNSCC），因为它精确地将辐射剂量传递到肿瘤并限制对周围正常组织的照射。然而，由于辐射剂量沉积的布拉格峰及其周围的能量减少（电离/线性能量转移增加），PBT的分子/细胞效应仍然存在显著的生物学不确定性。这就导致了临床上使用PBT治疗癌症患者的显著不确定性。此外，使用药物/小分子抑制剂的联合策略可以增强放射耐药癌症（包括HNSCC亚型）对PBT的敏感性尚不清楚，这可能与传统（x射线）辐射不同。这个mrc资助的DTP学生将开发新的PBT研究，研究参与细胞DNA损伤反应的关键酶（包括PARG， ATM， ATR和DNA- pk），作为克服HNSCC辐射耐药的靶标。这将通过使用已建立的二维细胞系、三维球体和患者来源的HNSCC类器官来实现。本项目在为HNSCC患者建立更有效的PBT临床管理和治疗方面具有很高的转化潜力。

Proton beam therapy (PBT) is increasingly being utilized worldwide for the treatment of specific cancers, such as head and neck squamous carcinoma (HNSCC), as it precisely delivers the radiation dose to the tumour and limits irradiation of surrounding normal tissues. However, there are still significant biological uncertainties of the molecular/cellular effects of PBT due to decreases in energy (increases in ionisation/linear energy transfer) at and around the Bragg peak where the radiation dose is deposited. This consequently leads to significant uncertainties in the use of PBT for the treatment of cancer patients in the clinic. Furthermore, identification of combinational strategies using drugs/small molecule inhibitors that can enhance sensitivity of radioresistant cancers, including subtypes of HNSCC, to PBT are unclear and which maybe distinct from conventional (x-ray) radiation.This MRC-funded DTP studentship will develop novel PBT research investigating key enzymes involved in the cellular DNA damage response (including PARG, ATM, ATR and DNA-Pk), as targets to overcome radioresistance of HNSCC. This will be delivered through the use of established 2D cell lines, 3D spheroids and patient-derived organoids of HNSCC. This project has high translational potential in the establishment of more effective clinical management and treatments for HNSCC patients using PBT.