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Intergrin inhibition in cancer therapy may depend on timing and cellular targeting
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The failure of drugs directed against the αvβ3-integrin in phase III clinical trials against aggressive brain cancer may be a result of not targeting the timing or cell type specificity of application of the antagonists precisely enough. That is the conclusion from new research published in Circulation Research and led by the laboratory of Prof. Stephen Robinson in the University of East Anglia (UEA). The group used knockout mice in which endothelial αvβ3-integrin was specifically targeted.

In order to grow and metastasise, solid tumours rely on angiogenesis, which means recruitment of their own blood supply from the existing vasculature that surrounds them. They achieve this by release of growth factors such as vascular endothelial growth factor (VEGF). A series of steps in the angiogenic process culminates in degradation of the endothelial cell basement membrane and the extracellular matrix (ECM), with proliferation of endothelial cells and their migration towards the tumour. These last parts of the process depend on integrins such as αvβ3-integrin, which is expressed in endothelial cells that have been stimulated by angiogenic growth factors and synergises with VEGF to promote angiogenesis. As such, αvβ3-integrin has been an attractive target for anti-angiogenic therapeutic drug strategies. However, the effectiveness of this integrin as a cancer drug target has been called into question by the failure of the αvβ3-integrin peptide antagonist Cilengitide to increase overall survival when administered along with standard chemotherapy in patients with aggressive brain cancer.

The study from UEA focused on knockout specifically of endothelial αvβ3-integrin, unlike previous studies which have adopted a global knockout approach. In these mice, the researchers found that the depletion of the endothelial αvβ3-integrin inhibited tumour growth and angiogenesis in a preventative manner but not in tumours that were already established. Similarly to the results obtained in the disappointing clinical trials, the protective effects were transient. The researchers hypothesised that other molecular changes that occurred from long-term αvβ3-integrin depletion, such as reduction in focal adhesion kinase (FAK) expression may provide an escape route from the inhibition of angiogenesis achieved initially by αvβ3-integrin-inhibition.

The researchers conclude that our current understanding of the best way to target anti- αvβ3-integrin reagents is too limited to allow this integrin to be abandoned as a potential tumour therapeutic target. This is especially in view of the fact that, unlike many other FDA-approved anti-angiogenic drugs, αvβ3-integrin antagonists are well-tolerated. Further studies are needed to establish better ways of using these antagonists in terms of timing of delivery to achieve prevention rather than using in an interventional regime and in terms of exploiting nanotechnology to allow endothelial targeting. The future may not be so bleak for anti- αvβ3-integrin reagents as possible cancer drugs.

Sources

Steri, V. Ellison, T.S., Gontarczyk, A.M., Weilbaecher, K., Schneider, J.G., Edwards, D., Fruttiger, M., Hodivala-Dilke, K.M. and Robinson, S.D. Acute Depletion of Endothelial beta3-Integrin Transiently Inhibits Tumour Growth and Angiogenesis in Mice. Circulation Research, January 2014. Epub Oct. 2013, PMID: 24103390

University of East Anglia. "Scientists make advance in cancer research." ScienceDaily, 3 Jan. 2014. [Accessed 6 Jan. 2014].
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Intergrin inhibition in cancer therapy may depend on timing and cellular targeting00