The focus of the group is on tumour angiogenesis and the role of notch signalling, and hypoxia biology and its regulation.
The aim of our research is to develop ways to improve the treatment of breast cancer and other tumour types, by blocking the blood supply to tumours. Our special interest is in breast cancer and mechanisms of resistance to therapy, regulated by hypoxic metabolism and tumour angiogenesis, when tumours cannot grow without a new blood supply developing from pre-existing blood vessels. Our research focusses on tumour angiogenesis and the role of notch signalling, and hypoxia biology and its regulation. New angiogenesis pathways involving notch signalling and G-coupled receptors have been discovered and therapeutic antibodies have been developed against them. We want to translate these basic discoveries into clinical relevance.
Hypoxia regulates many oncogenic pathways, as well as tumour angiogenesis, and it produces major metabolic changes. The latter may be responsible for resistance to endocrine therapy, chemotherapy and radiotherapy through different pathways. Our preclinical programme investigates several of these, and particularly those involved in lipid and glycogen metabolism. These provide new therapeutic avenues that will be assessed in Phase 1 and Phase 2 studies. A major interest is in new angiogenic therapies, and developing ways to determine who will most benefit from these targeted therapies. Our work assesses the short term effects on imaging with novel scanning agents, and biopsies for gene expression, then relates tumour response to longer term outcomes. In addition, metabolic profiling will be undertaken in patients to correlate the responses to new therapies with imaging changes and for individualisation of therapy.
Preclinical work has indicated combination therapy is significantly better and that the induction of hypoxia may induce a synthetic lethality approach, targeting the hypoxic pathways induced by antiangiogenic therapy. Many of these are also involved in the induction of tumour angiogenesis. The metformin study started because metabolic changes induced by Avastin® could be antagonised by metformin and combination therapy may therefore be a useful new modality. However, patients will respond differently to metformin based on the cancer cell biology and we want to try to identify those who show the clearest benefits and elucidate the pathways responsible.
Spectrum of DCE-MRI response to Bevacizumab
We investigated 40 patients with breast cancer due to undergo neoadjuvant chemotherapy. They received 15mg/kg I.V. Bevacizumab (Avastin), 2 weeks before chemotherapy. This showed a spectrum of response on DCE-MRI within the 2 weeks. There were tumours where the ‘vascular rim’ markedly decreased without evidence of tumour cell death; those rarely with central necrosis and markedly decreased vessels; and finally those which grew straight through the therapy with an increase in rim perfusion.
Adrian Harris has been the Cancer Research UK Professor of Medical Oncology in the Department of Oncology at University of Oxford since 1988 and is also a Professorial Fellow of St Hugh's College, University of Oxford. He is a Consultant Medical Oncologist at the Oxford University Hospitals NHS Trust. He was also the Director of Molecular Oncology Laboratory at the University of Oxford. He trained in Medicine and Biochemistry at Liverpool University and subsequently received his DPhil from Oxford University. He then trained at the Royal Marsden Hospital in Medical Oncology.
Kerr, G., Sheldon, H., Chaikuad, A., Alfano, I., von Delft, F., Bullock, A.N., and Harris, A.L. (2015). A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. Angiogenesis 18, 209-217.
Leung, W.Y., Roxanis, I., Sheldon, H., Buffa, F.M., Li, J.L., Harris, A.L., and Kong, A. (2015). Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer. Oncotarget 6, 5678-5694.
Lewis, C.A., Brault, C., Peck, B., Bensaad, K., Griffiths, B., Mitter, R., Chakravarty, P., East, P., Dankworth, B., Alibhai, D., Harris, A.L., and Schulze, A. (2015). SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene.
McIntyre, A., and Harris, A.L. (2015). Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol Med 7, 368-379.