How does the tumour microenvironment affect cancer cell responses to DNA damage repair inhibition during radiotherapy?

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 as an anti-cancer target. DNA Polymerase theta 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 DNA Polymerase theta 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.
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. 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 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.

This project will lead to a greater understanding of how different tumour microenvironments affect cancer cell responses to DDR inhibitors and radiation therapy. This is an aspect of radiobiology that is not well studied and the beneficiaries of this project will be the DNA repair and the cancer metabolism fields. We expect to publish the results of this project in a high impact cancer journal.
The University and the academic partner will also mutually benefit from this partnership. The University will get unique access to novel DDR inhibitors and technical expertise from the commercial partner. The commercial partner will benefit from our expertise and facilities that simulate the microenvironmental conditions, advanced radiation technology, as well as our collaborations with metabolomics facilities. We anticipate this will provide valuable experimental results on the behaviour of their compounds in different biological settings.

This project will have a strong translational focus to help guide the design of clinical trials for these compounds and the stratification of future patients.