Title: Role of notch signalling and hypoxia in resistance to anti-angiogenic therapy
Funder: Cancer Research UK

Abstract: Tumours require a new blood supply to grow - angiogenesis. Blocking angiogenesis is an important new treatment for cancer. We aim to discover new pathways that regulate tumour angiogenesis and understand how cancers develop resistance to current antiangiogenic therapies. These studies will provide new targets for therapy and improve existing treatments. Last updated 18/08/2009 Background Tumours require angiogenesis to grow and metastasise. Vascular endothelial growth factor (VEGF) is one of the key angiogenic factors, regulated by hypoxia, and it is effective for treating several types of cancer. However, resistance is common both de novo and after initial response to therapy. This implies different mechanisms of angiogenesis are important initially, and adaptation to the environmental stresses, including hypoxia, induced by the antiangiogenic therapy. Relevance to cancer Understanding new pathways of tumour angiogenesis and how they relate to resistance to current therapies will provide new targets for therapy. Understanding how cancer cells adjust to a high stress environment, gives us the opportunity to use synthetic lethal approaches for therapy, which should have low normal tissue toxicity. Specific aims of the research 1. To investigate the role of notch signalling in tumour angiogenesis and in resistance to anti-VEGF therapy. 2. To investigate the survival pathways in tumour and stroma produced by hypoxia in response to inhibition of notch and VEGF signalling. The changes in metabolic and mitochondrial pathways and the induction of bypass angiogenic pathways will help provide new approaches to anti-angiogenic therapy. Outline plan of research 1. Mechanisms of notch regulation of angiogenesis. We will investigate genes induced by delta-like 4, an endothelial specific notch ligand regulated by hypoxia, in human endothelial cells using CAGE analysis. Those most upregulated and relating to cell signalling and cell surface proteins will be investigated in in vitro models of 3D vessel growth and zebra fish embryos with fluorescently tagged vessel markers. This will allow us to select genes most critically involved in angiogenesis and development of antibodies or small molecule inhibitors against them. 2. Gene array analysis of tumour xenografts and stroma under therapy with notch inhibitors or VEGF inhibition has shown commonality of responses, including major changes in lipid and glutamine metabolism. We will regulate the key enzymes concerned, with inducible vectors and small molecule inhibitors, to determine those most critical for tumour survival. 3. We will screen an shRNA library for synthetic lethality with hypoxia in human cancer cell lines. 4. Carbonic anhydrase 9 is critical for cell survival in hypoxia. We will investigate its role in survival in vivo, its contribution to resistance to anti-angiogenic therapy and survival of self renewing populations. 5. Many mitochondrial genes are markedly suppressed by hypoxia, but we have found the mutant mitochondrial enzyme AK3L is induced and critical to cell survival. Its role will be investigated by knockdown and analysis of interacting proteins. Last updated 18/08/2009


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS