Quantifying the impact of DNA repair dysregulation on intrinsic radiation sensitivity

Varied genetic alterations mean different patients’ cancers respond differently to radiation therapy, which can significantly impact on patient outcome. If the impact of these alterations can be understood and quantified, it could provide the basis for a tool to tailor radiotherapy treatments based on individual biology. Developing a better understanding of the intrinsic sensitivity of different cancers to radiation remains a major goal to support the delivery of personalised radiation therapy. While a range of processes are known to impact on response, such as the cells’ ability to repair DNA damage or how sensitive it is to misrepaired DNA, these effects are often poorly quantified and so cannot be used as clinical predictive tools. Ongoing work within our centre seeks to develop new tools to quantitatively predict how sensitivity depends on these processes to help to translate this knowledge to the clinic.

This PhD will contribute to this effort, working as part of a team to characterise key aspects of radiation response and how it depends on common genetic variants in cancer. In particular, this project will focus on the impact of alterations in DNA repair pathways which are commonly activated following radiotherapy. Investigating how cellular sensitivity to radiation changes when key genes are mutated or removed will enable the quantification of the impact of these pathways, and the underlying processes will be confirmed through mechanistic validation. The candidate will then work in collaboration with other members of the team to integrate this knowledge into predictive models of radiation

sensitivity, which will be validated against both preclinical and clinical data.