How does the tumour microenvironment affect cancer cell responses to DNA damage repair inhibition during radiotherapy?
LEAD SUPERVISOR: Dr Geoff Higgins, Department of Oncology
Co-supervisor: Professor Amato Giaccia, Department of Oncology
Commercial partner: Artios Pharma Limited, Cambridge
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. 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.
Apply using course: DPhil in Oncology