Integrin inhibitors are being investigated to treat cancer, but new research suggests they could actually promote tumour growth
Several integrin inhibitors are in clinical trials for the treatment of cancer. But a group of scientists has found that at low doses these drugs might actually have the opposite effect and promote tumour growth.
Integrins are receptors on the surface of cells that play a number of roles, including defining cellular shape, mobility and regulating the cell cycle. In lab tumour models, blocking the action of integrin inhibits the angiogenesis process - the growth of the new blood vessels a tumour needs to survive and grow - which makes them an attractive target for potential drug therapy.
However, although they suppress tumour growth in preclinical trials, these drugs have not proved as successful in human clinical trials as had been hoped. ’Although one of these drugs, cilengitide [from Merck KGaA], has had some success in some brain tumours, we wanted to know why these agents weren’t working as well as they could, especially in other, resistant, tumour types,’ explains Kairbaan Hodivala-Dilke of Cancer Research UK’s Clinical Centre at the Institute of Cancer in London.
The scientists realised these drugs can reach very low concentrations in patients because they are metabolised and excreted quite fast. ’We decided to test low versus high doses of these agents on tumour growth and angiogenesis directly,’ she said. ’We found evidence that low concentrations of integrin inhibitors can, in fact, enhance tumour growth by promoting tumour angiogenesis.’ They think this may be because it encourages angiogenesis mediated by vascular endothelial growth factor, or VEGF.
’This may be one of the reasons why these drugs are not working in more types of cancer,’ explains Andrew Reynolds of the Institute of Cancer Research, who was also involved in the study. Cilengitide blocks the integrin
3, and Reynolds says that their next step is to look at other
3 inhibitors which might have higher affinity for the receptor, or perhaps inhibit it by a different mechanism. These might be better at blocking angiogenesis, even at low doses.
Several other integrin inhibitors are currently in clinical trials. Cilengitide is the furthest advanced, in Phase III trials, and two monoclonal antibodies are in Phase II. Vitaxan from MedImmune targets the same integrin as cilengitide, and Biogen Idec’s volociximab blocks a different integrin,
1. Pfizer, Eisai and Centocor are also working in the area.
Reynolds says that future research could take them in several directions. ’We also want to address whether
3 inhibitors can perform better if they are combined with other drugs, and we want to know if low doses of other angiogenesis inhibitors can also promote tumour growth,’ he says.
et al.Nature Medicine, 2009. DOI: doi:10.1038/nm.1941