How does tumour metabolism affect the efficacy of DNA damage response inhibitors?
LEAD SUPERVISOR: Prof Geoff Higgins, Department of Oncology
Co-supervisor: Prof Tim Humphrey, Department of Oncology
Commercial partner: Artios Pharma Ltd, Cambridge
The tumour microenvironment can impact the efficacy of cancer treatment. One of the best-known examples is tumour hypoxia, which is known to greatly diminish the effectiveness of radiotherapy. We have recently shown that by modulating the way tumour cells consume oxygen, we can reduce tumour hypoxia and improve radiotherapy efficacy.
Another way to improve radiotherapy efficacy is by increasing the intrinsic radiation sensitivity of tumour cells. DNA damage response (DDR) inhibitors are promising novel molecular agents that can inhibit the cancer cell’s ability to repair the DNA damage inflicted by radio- and chemotherapy, enhancing therapeutic efficacy. They can also be effective as single agents in selected patient populations with tumours carrying lesions in DNA repair genes that display “synthetic lethality” with the DDR inhibitors. Our group was one of the first to identify DNA Polymerase theta (Polq) as an anti-cancer target. Polq is a specialised DNA repair enzyme with low expression in most normal tissues but frequently overexpressed in many cancer types, thus representing an ideal target to specifically increase tumour sensitivity to radiotherapy or other treatment modalities. For this project, we have unique access to potent and first-in-class Polq inhibitors developed by the commercial partner, Artios Pharma. These inhibitors have been shown to cause synthetic lethality in susceptible tumour cells and mediate tumour specific radiosensitisation.
Recent evidence has shown that tumour metabolism can affect the way tumour cells repair DNA damage. It is therefore likely that efficacy of DDR inhibitors is also affected by metabolic and environmental factors within the tumour. The aim of this project is to investigate how environmental conditions such as hypoxia and metabolic pathways (e.g. glycolysis versus oxidative phosphorylation) affect sensitivity to Polq inhibitors and other DDR inhibitors and explore the mechanism behind any alterations in sensitivity. This will be investigated in 2D and 3D tumour models with the potential to extend this to in vivo models.
This collaboration will synergise our group’s expertise in the tumour microenvironment with the DDR expertise of our commercial partner. Artios Pharma is a leading independent DNA Damage Response company, whose portfolio include Polq, ATR and DNA nuclease inhibitors. They will provide proprietary DDR inhibitors, which the student will test in different microenvironmental conditions. This will include hypoxia chamber experiments, which cannot easily be done at Artios. During the stay at Artios, the student will perform techniques that are not available at the University, including molecular DNA repair assays and high content microscopy linked to DNA repair monitoring in different metabolic conditions. Together the results obtained at Oxford and Artios will provide new insight in DDR inhibitor efficacy and the tumour microenvironment and it is hoped that this will help the design of upcoming clinical trials and guide future patient stratification.
Apply using course: DPhil in Oncology