Integrin Inhibitors Can Boost Rather than Block Tumour Cell Growth

tumour angiogenesisTo grow beyond a certain size, solid tumours need to secure an adequate blood supply and are able to induce angiogenesis to achieve this. Many modulators of angiogenesis have been identified including growth factors such as vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), integrin and cadherin adhesion molecules, and matrix-degrading enzymes. Although angiogenesis inhibitors that target the VEGF pathway such as bevacizumab (Avastin™) and sunitinib (Sutent™) have shown good results in some patients, trials of integrin inhibitors have generally proved less successful.

cilengitide structureIntegrins are cell surface receptors that play a role in defining cell shape, attachment, and mobility as well as in signal transduction and regulation of the cell cycle. Research funded by Cancer Research UK now suggests that the lack of clinical efficacy of integrin inhibitors may be due to insufficient levels of drug in the body. In laboratory studies, low levels of the experimental integrin inhibitor, cilengitide, were found to boost rather than block tumour cell growth. Cilengitide is a cyclic Arg-Gly-Asp peptide which, at higher doses, binds to and inhibits the activities of the αvβ3 and αvβ5 integrins, thereby inhibiting endothelial cell-cell interactions, endothelial cell-matrix interactions, and angiogenesis. The research, which is published in the journal Nature Medicine, found that low (nM) doses of cilengitide stimulated the supply of blood to the tumour and promoted its growth. Although very low doses of the drug did not have a direct effect on cancer cells, when they were grown alongside blood vessel cells low levels of cilengitide boosted growth of the cancer cells. Low concentrations of cilengitide were shown to promote VEGF-mediated angiogenesis by altering αvβ3 integrin and VEGFR2 trafficking, promoting endothelial cell migration to VEGF.

Even when high doses of cilengitide are administered to patients, blood levels fall in a few hours down to the levels that stimulated rather than blocked tumour growth, suggesting a reason for the poorer than expected efficacy in clinical trials. The study suggests that changing the route of administration or dosing schedule of integrin inhibitors may enhance their clinical efficacy.

Note added 25/3/09, 16.15: Merck Serono released a statement regarding media coverage on pre-clinical integrin inhibitor study in animal model, published in Nature Medicine (22nd March 2009), stating:

Isolated preclinical animal experiment findings do not reflect the actual clinical experience.

The press release can be seen here.

New Insight into Mechanism of VEGF Inhibitors

angiogenesisVascular endothelial growth factor (VEGF) is an important signalling molecule which contributes to angiogenesis. Since angiogenesis is believed to be essential for the growth and metastasis of tumours, blocking the VEGF pathway is considered to be a viable antitumor strategy and both antibodies to VEGF and small molecule inhibitors of VEGF-stimulated tyrosine kinases are used as chemotherapy. Now, a study carried out by researchers at the University of California suggests that dense networks of blood vessels formed during angiogenesis could impede rather than promote the growth of tumours. Inflammatory cells, which infiltrate many tumours, provide a source of VEGF and the team created a strain of mice in which most of the inflammatory cells lacked the gene for VEGF. These mice were then crossed with a strain of mice which reliably develop mammary tumours. Although blood supply to the tumours in the VEGF-deficient mice was reduced, the blood vessels looked more normally organised and less leaky than in the non-engineered mice.

All of the mice developed tumours by 20 weeks of age, but the mice with low levels of VEGF had larger growths that were more likely to have progressed to a later stage of cancer. Although the tumours grew faster in the VEGF-deficient mice, importantly, they were also more susceptible to two different chemotherapy drugs. The study suggests a reason why blocking the effect of VEGF is less effective as monotherapy for cancer than when used in combination with traditional chemotherapy drugs: reduced levels of VEGF lead to more normal blood vessels that are better able to deliver the drugs to the tumour. The findings are published in the 9 November online edition of the journal, Nature.