Angiogenesis inhibitors, current drugs and new targets
Adrian Harris
Weatherall Institute of Molecular Medicine, University of Oxford, UK
There are many pathways that induce angiogenesis but vascular endothelial growth factor (VEGF) is one of the most highly and frequently expressed, regulates and is synergistic with many pathways. There has been substantial success demonstrating that VEGF is a valid target and inhibition of VEGF by Avastin in several tumour types; Sorafenib in renal cancer and hepatoma and Sutent in renal cancer have all improved patient outcomes, either alone or in combination therapy.
However, overall the majority of tumours are still resistant to these agents and survival is prolonged by several months rather than years. Thus we need to understand more about mechanisms of resistance to VEGF as well which tumours are most sensitive and why. Mechanisms may be vascular co-option, different angiogenic pathways, insufficient drug penetration or sufficient high levels of VEGF to overcome therapeutic inhibition and the ability to survive hypoxia.
We have recent evidence that up-regulation of NOTCH signalling in tumourvasculature can play a substantial role. Using human cancer cell lines transfected with the endothelial NOTCH ligand, delta like 4 showed a marked change in the tumour vasculature. The vessels became less branched, larger and better functionally. They also became resistant to the effect of Avastin and also low MW inhibitors of VEGF receptors. Using small molecular inhibitors of gamma secretase had a small effect on tumour growth, but markedly synergised with Avastin. It seems to be a result of blocking a feed back loop whereby NOTCH signalling down-regulates VEGF-R2. The combination of treatments using these approaches may be valuable in certain sub-sets of patients.
We need to stratify our patients in advance of therapy, to select which antiangiogenic drugs might be most appropriate. We have been using gene array analysis and this has generated a hypoxia metagene, applicable to most tumor types so far studied. Also immunohistochemistry, focusing on expression of the lactate dehydrogenase A isoform LHD5 complex induced by HIF1a, we showed that it correlates strongly with other pathways, such as VEGF and VEGF R2 phosphorylation and HIF1a in colorectal cancer and with response to low MW VEGF inhibitors [PTK 787].
