Lay summary
Radiotherapy, in combination with chemotherapy, is used to treat advanced head and neck squamous cell carcinoma (HNSCC), but tumour control within the radiation field is limited by normal tissue toxicity and tumour hypoxia. We have identified novel DNA-PK inhibitors which sensitise HNSCC cells and tumours to radiation. We will exploit the presence of hypoxic cells in HNSCC tumours using prodrugs to selectively deliver the DNA-PK inhibitor. We will prepare and evaluate a series of prodrugs in HNSCC models to identify a lead prodrug. We will develop models of the behaviour of the prodrug in tumours and predict the best way to administer the prodrug. We will evaluate the prodrug's ability to radiosensitise HNSCC tumour xenografts and determine the advantage the prodrugs provide through sparing normal tissue and selectively killing tumour cells. We will work with Māori groups to identify pathway to equitable clinical application of this novel prodrug.