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Primary Supervisor: Dr Geoffrey Higgins

Project Overview:

Our research aims to develop therapies that selectively exploit tumour responses to improve radiotherapy efficacy and tolerability. We are interested in how DNA damage sensitivity can be modulated under radiation and in diverse tumour microenvironments and metabolic backgrounds. Our work is strongly aligned with the MRC’s themes of developing precision medicine and advanced therapies.

DNA damage response (DDR) inhibitors are promising novel molecular agents that inhibit cancer cell’s ability to repair the DNA damage from radio- and chemotherapy, enhancing their therapeutic efficacy. Our group was one of the first to identify DNA Polymerase theta (Polq) as an anti-cancer target. Polq has low expression in most normal tissues but is frequently overexpressed in many cancer types, representing an ideal tumour-selective target. We have a long-standing collaboration with our commercial partner (Artios) in testing potent first-in-class Polq inhibitors which have now progressed to clinical trials. Together, we have recently demonstrated that these inhibitors cause synthetic lethality in homologous recombination deficient tumour cells (Nat Comms DOI: 10.1038/s41467-021-23463-8).

Our group has shown that Polq inhibitors can mediate tumour specific radiosensitisation (manuscript under review). Further elucidation of cellular backgrounds and tumour environmental conditions that enhance radiotherapy and Polq inhibitor efficacy can help expand the clinical application of these compounds.

The metabolic plasticity of tumour cells is influenced by microenvironmental changes and is implicated in resistance to DNA damaging therapies, and therefore a key target to explore in improving therapeutic efficacy. 

Tumour hypoxia confers resistance to many cancer treatments particularly radiation therapy. The Higgins group has recently developed compounds to reverse tumour hypoxia which have progressed to clinical trials, whilst the Giaccia group has recently demonstrated that targeting hypoxic cells can be an effective strategy in improving the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors. 

The expertise of both the Higgins and Giaccia groups in clinical translation, tumour metabolism, hypoxia, and radiotherapy responses will synergise with the DDR and drug development knowledge base of our commercial partner, Artios Pharma Ltd. This project will screen diverse cancer cell lines for vulnerabilities that arise from different tumour microenvironmental conditions (i.e. hypoxia, low glucose etc.) in response to DDRi (including Polqi) and radiation treatments. This project will start with 2D models, with the potential to continue to 3D in vitro and in vivo models. The University of Oxford will provide the facilities to conduct high-quality research in this area, including hypoxia chambers, specialised irradiators (e.g., ultra-soft x-rays and FLASH irradiation), as well as academic collaborations for targeted and untargeted metabolomics. Artios Pharma is a leading independent DNA Damage Response company, who will provide the novel inhibitors for the student to test as well as training and access to techniques unavailable at the university. This will include molecular DNA repair assays and high content microscopy linked to DNA repair monitoring.

Together, the results obtained at Oxford and Artios will provide new insights on DDR inhibitor efficacy, the tumour microenvironment and cancer metabolism in relation to radiation therapy. It is hoped that this work will help the design of future trials and guide patient stratification.

Training Opportunities:

This collaborative project will provide unique opportunities for a PhD student to experience both sides of academic and industrial cancer research, including the exposure to the drug discovery and development pipelines that has high relevance for translational research. 

The student will have access to a diverse range of radiation technologies, including gamma irradiators, ultra-soft x-ray irradiators for DNA repair studies, Small Animal Radiation Research Platform (SARRP) image guided pre-clinical irradiators, and linear accelerators for FLASH radiotherapy. Our group also has a strong collaborative relationship with the Chemistry Department, particularly the McCullagh Group which runs the advanced metabolomics facilities. The student will be able to work with their group to assess the metabolic profiles of both cells and whole tissue.

In Artios Pharma, the student will have access to a variety of specialised techniques and approaches that will be pivotal to advance the collaborative project. This will include assays specifically designed to measure the proficiency and activity of different DDR pathways (including homologous recombination, non-homologous end-joining, and microhomology-mediated end-joining), which can be applied to study how perturbations of the microenvironment or treatment with DDR inhibitors affect DNA repair.  The student will be trained to use real time fluorescent microscopes to study the kinetics and the mechanism of cell death in time-course experiments. Additionally, the student will learn to quantify the induction of DDR markers using established experimental protocols for Western blot, immunofluorescence (DDRi foci) and flow cytometry. The student will be trained by the supervisors or experienced scientists in Artios and, if necessary for specific techniques and instruments, ad hoc training courses can be arranged.