Targeting hypoxia metabolism and angiogenesis for synthetic lethality.
The overall aims are to investigate new pathways of tumour angiogenesis and mechanisms of hypoxia survival that allow tumour cells to continue to survive and grow. Although antiangiogenic therapies are effective, current drugs induce hypoxia and rapid metabolic adaptation. Understanding which pathways are most important for survival in hypoxia may allow selective targeting and synthetic lethality.
Our approach takes into account new developments in technologies and concepts, to which we have contributed, on resistance mechanisms to angiogenic therapies.
1. Investigate mechanisms of action and function of ELTD1 in tumour angiogenesis. This new pathway we discovered is upregulated in the vasculature of many cancer types and downregulation inhibited growth of the primary tumour and metastases in xenografts. Understanding this pathway would contribute to new therapy approaches and modification of effects of standard therapies including radiation.
2. Investigate resistance of tumour endothelium to radiation therapy [RT]. Our initial data had found induction of interferon signalling response [lFR] was important for adaptation in endothelium, and regulation of this pathway by DNA repair enzymes greatly modified sensitivity. Isolation of endothelial cells from primary human cancers and analysis of their adaptive mechanism is planned. Analysis of how hypoxia affects the IFR is ongoing.
3. Elucidate the role of glycogen metabolism in tumour survival and role other metabolic genes shown by bioinformatic analysis. From our clinical and xenograft data, we could see that survival in poorly oxygenated low vascularity area allowed tumours to regrow. We had discovered a key role of hypoxia-induced glycogen storage, and block of its degradation enhanced effects of radiation. This provided a potentially important link to therapy, as inhibition could synergise with both antiangiogenic and radiation therapy,
4. Investigate the mechanisms and relevance of heterogeneity of the hypoxia response. The heterogeneity of tumour hypoxia is obvious, but we had found transient hypoxia exposure selected within 3 days subpopulations with different hypoxia responses maintained for many months and planned to investigate the metabolic cooperation between these populations and basis for the regulation.
New technologies and concepts:
Recognition of the role of vascular co-option in resistance to antiangiogenic therapy [reviewed by us Non-angiogenic tumours and their influence on cancer biology. Nature reviews Cancer (2018). 18, 323-336]
The use of Chromium 10X sequencing to analyse the heterogeneity of endothelial cell responses to antiangiogenic therapy and cancer cells to hypoxia. This will allow us to investigate the biology r of vascular co-option.
Our extensive bioinformatic analysis demonstrated gene amplification of metabolism enzymes and their association with hypoxia on TCGA data. In combination with an siRNA screen incorporating that information, has led to the discovery of the role of amplified PDE6H, a potential modifier of RAS signalling.
The application of our previous work on hypoxia profiles and angiogenesis has supported clinical window studies of hypoxia and metabolism in breast cancer, with bevacizumab and metformin.
Prof Peter McHugh, Department of Oncology, University of Oxford
Prof Jan Rehwinkel, MRC Human Immunology Unit, University of Oxford
Prof Francesca Buffa, Department of Oncology, University of Oxford
Dr Karl Morton, Nuffield Department of Obstetrics and Gynaecology, University of Oxford
Prof Alison Banham, Radcliffe Department of Medicine, University of Oxford
Prof Sarah Blagden, Department of Oncology, University of Oxford
Prof Jane McKeating, Nuffield Department of Medicine, University of Oxford
Prof Chris Pugh, Nuffield Department of Medicine, University of Oxford
Prof Vincenzo Cerundolo, MRC Human Immunology Unit, University of Oxford
Prof Deborah Goberdhan, Department of Physiology, Anatomy and Genetics, University of Oxford
Prof Ioannis Ragoussis, Genome Sciences, McGill University and Genome Quebec Innovation Centre, Canada