Abstract
Cancer cells rely on angiogenesis to fulfil their need for oxygen and nutrients; hence, agents targeting angiogenic pathways and mediators have been investigated as potential cancer drugs. Although this strategy has demonstrated delayed tumour progression—leading to progression-free survival and overall survival benefits compared with standard therapy—in some patients, the results are more modest than predicted. A significant number of patients either do not respond to antiangiogenic agents or fairly rapidly develop resistance to them, which raises questions about how resistance develops and how it can be overcome. Furthermore, whether cancers, once they develop resistance, become more invasive or lead to metastatic disease remains unclear. Several mechanisms of resistance have been recently proposed and emerging evidence indicates that, under certain experimental conditions, antiangiogenic agents increase intratumour hypoxia by promoting vessel pruning and inhibiting neoangiogenesis. Indeed, several studies have highlighted the possibility that inhibitors of VEGF (and its receptors) can promote an invasive metastatic switch, in part by creating an increasingly hypoxic tumour microenvironment. As a potential remedy, a number of therapeutic approaches have been investigated that target the hypoxic tumour compartment to improve the clinical outcome of antiangiogenic therapy.
Key Points
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Antiangiogenic therapy has been widely used in clinical trials, with delayed tumour progression in some patients leading to improved progression-free survival and overall survival compared with standard therapy
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Unfortunately, a significant number of patients either do not respond to antiangiogenic therapy or rapidly develop resistance to it
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Vessel pruning and inhibition of neoangiogenesis leading to intratumour hypoxia is one of several proposed mechanisms explaining resistance to antiangiogenic therapy
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Hypoxia is a key mediator of tumour progression that regulates cancer cell survival, metabolic switch, genomic instability, angiogenesis and selection of a more aggressive phenotype
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Combining antiangiogenic therapies with hypoxia-targeted strategies might fully exploit the potential of hypoxia-dependent response inhibition, as well as prevent resistance to inhibitors of the proangiogenic factor VEGF
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A major requirement for combining antiangiogenic agents with hypoxia-targeted strategies is the development of robust predictive biomarkers for patient selection
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Change history
21 May 2012
In the version of this article initially published online, the legends of Tables 1 and 2 should have included the attribution: Permission obtained from Nature Publishing Group © Ebos, J. M. L. & Kerbel, R. S. Nat. Rev. Clin. Oncol. 8, 210–221 (2011). The error has been corrected for the print, HTML and PDF versions of the article.
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Acknowledgements
The authors would like to thank Nicole Fer and Monica Mancini for their helpful discussions. This study was supported in part with federal funds from the National Cancer Institute, NIH, under Contract No. N01-CO12400. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services. Any mention of trade names, commercial products or specific organizations does not imply endorsement by the US Government. This research was supported (in part) by the Developmental Therapeutics Program, DCTD, of the National Cancer Institute, NIH.
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Rapisarda, A., Melillo, G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9, 378–390 (2012). https://doi.org/10.1038/nrclinonc.2012.64
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DOI: https://doi.org/10.1038/nrclinonc.2012.64
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