Exploiting Tumour Vulnerabilities to Improve Radiotherapy Efficacy

Primary Supervisor: Dr Geoff Higgins

Second Supervisor: Dr Gonzalo Rodriguez Berriguete

Project Overview

Radiotherapy (RT) remains a cornerstone in the treatment of many solid tumours, offering the potential for curative intervention either as a standalone modality or in combination with chemotherapy or immunotherapy. Technological advances—such as stereotactic ablative body radiotherapy (SABR)—have significantly improved the precision and efficacy of RT delivery. However, even with these innovations, the unavoidable exposure of surrounding healthy tissue to ionising radiation often results in significant and sometimes dose-limiting toxicities. Efforts to improve tumour control by simply escalating RT dose are constrained by these normal tissue effects. A more promising strategy involves the development of tumour-selective radiosensitising agents—therapies that enhance tumour sensitivity to radiation while sparing normal cells. This approach could allow for more effective tumour control without increasing toxicity. Our group has undertaken high-throughput chemical and genetic screening efforts to identify candidate radiosensitising targets and compounds with clinical translation potential. As a result, we have established a panel of promising targets and associated compounds that form the basis of this project. The primary aim of this DPhil will be to characterise the biological function and therapeutic potential of these candidates in the context of RT, using a combination of in vitro and in vivo models. The project will also involve the development and optimisation of therapeutic strategies to exploit these vulnerabilities in tumours. Ultimately, this research is geared towards preclinical validation and future clinical translation, with the overarching goal of improving outcomes for patients undergoing radiotherapy.

Training Opportunities

This DPhil project provides an excellent training environment in cancer biology and therapeutic development. The student will gain hands-on experience in high-throughput screening, CRISPR-based gene editing, RNA interference, cell death and viability assays, DNA damage response analysis, and cell cycle profiling. For those interested, optional training in in vivo cancer models is available, offering insights into tumour biology and therapy assessment in a physiological context. The student will participate in lab meetings, seminars, and present at national and international conferences. A wide range of training courses will support their scientific and professional development. The project also offers opportunities to collaborate with academic and industry partners, bridging the gap between basic research and clinical translation. This programme is well-suited to motivated individuals aiming to develop as independent, interdisciplinary researchers working at the interface of laboratory science and therapeutic innovation.

References

Rodriguez-Berriguete, G., Thambiayah, P., Cicconi, A., Machado, N., Gotorbe, C., Nderitu, D., Cheng, W.C., Boursier, M.L., Cerutti, A., Grinkevich, V. and Hill, B.R., 2025. SHLD2 loss is a synthetic vulnerability to Polθ inhibition combined with radiotherapy. bioRxiv, pp.2025-07.

https://www.biorxiv.org/content/10.1101/2025.07.04.662969.abstract