UK scientists found that a type of angiogenesis inhibitor used to treat cancer can actually encourage rather than stop tumour growth when given at low doses.
The researchers who carried out the study are from the The Institute of Cancer, Queen Mary, University of London, the Institute of Cancer Research (ICR), a college of the University of London, and the Beatson Institute for Cancer Research, Glasgow and they published their findings in the 22 March online issue of Nature Medicine.
Angiogenesis inhibitors are designed to stop tumours growing by cutting off their blood supply. They work by changing the way molecules that control cell behaviour send signals to each other, a very complex process.
In this study, lead investigator Dr Kairbaan Hodivala-Dilke of The Institute of Cancer and colleagues focused on an experimental angiogenesis inhibitor called cilengitide that has not yet been licensed for patients.
This type of angiogenesis inhibitor targets integrins, cell receptors that help to regulate how cells stick to other cells and to the cell-matrix (tissue that is not part of a cell) and also play a role in processing signals that pass between cells and regulate many important processes like growth, wound healing, and immune system function.
In this study, the researchers showed through laboratory studies that cilengitide can change the way integrins and VEGF receptors move inside blood vessels. Vascular Endothelial Growth Factor (VEGF) is a protein that stimulates growth of blood vessels.
They found that this type of angiogenesis inhibitor can actually promote cell growth and blood vessel formation instead of blocking it because it changes the way that integrin and VEGF receptors move inside blood vessels
The researchers also suggested that what they have found could be a previously unknown characteristic of drugs similar to cilengitide.
Sometimes just a small change in the way a drug is used, or a small change to its composition can have a very large effect on how it works, said Dr Lesley Walker, director of cancer information at Cancer Research UK who said this study was important because:
“It may help to explain the mixed results previously seen in patients and turn around disappointing results so people may still benefit from the drug without the potential harm.”
“Other anti-angiogenesis drugs like sunitinib (Sutent) and bevacizumab (Avastin) have proven effective enough for use in the NHS but there is still need to understand why they can sometime fail. It may be that there are similar mechanisms at work,” she added.
Another paper published this month in the journal Cancer Cell shows that sunitinib (Sutent), can sometimes encourage tumour growth rather than stunt it.
Hodivala-Dilke told the BBC that:
“We’ve got evidence now that low doses [of cilengitide] can enhance tumour growth. So there is no benefit of giving a high dose, which then drops, and then a high dose again.”
However, this does not mean it won’t work at all, and it is important that the trials continue, she added, “but there is this caveat”.
She explained that it might be more effective to give the drug via an infusion pump which would keep the dosage at the right level.
Co-investigator Dr Andy Reynolds, of the Breakthrough Breast Cancer Research Centre at the ICR, said in a press statement:
“Our study revealed a previously unknown mechanism through which drugs such as cilengitide behave.”
“These results may explain why initial results from early stage clinical trials have not been as promising as hoped,” said Reynolds.
“Knowledge of this mechanism will help us develop new ways to make these drugs as effective as possible. In the future, we may be able to combine these inhibitors with other drugs to maximise their effectiveness for patients,” he added.
“Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.”
Andrew R Reynolds, Ian R Hart, Alan R Watson, Jonathan C Welti, Rita G Silva, Stephen D Robinson, Georges Da Violante, Morgane Gourlaouen, Mishal Salih, Matt C Jones, Dylan T Jones, Garry Saunders, Vassiliki Kostourou, Francoise Perron-Sierra, Jim C Norman, Gordon C Tucker, Kairbaan M Hodivala-Dilke.
Nature Medicine (22 Mar 2009).
doi: 10.1038/nm.1941
Sources: Journal abstract, Cancer Research UK, BBC, National Library of Medicine (NIH, MesH Descriptor data).
Written by: Catharine Paddock, PhD