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Improving treatment of liver metastases by targeting nonangiogenic mechanisms

Nature Medicine volume 22, pages 1209–1210 (2016)Cite this article

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A recent study confirms an association between vessel co-option and resistance to bevacizumab, an anti-vascular endothelial growth factor-A (VEGFA) antibody, in patients with liver metastases. The authors suggest a combined therapeutic strategy that reduces co-option in mice.

Since 2004, a dozen drugs that target either VEGFA or its receptors have been approved for the treatment of ten different malignancies. In randomized phase 3 trials, these drugs have provided overall survival benefits on the order of weeks to months in some malignancies (for example, metastatic colorectal cancer), but none in others (for example, glioblastoma and metastatic breast cancer)1. Thus, identifying and targeting mechanisms of resistance to anti-VEGFA agents, as well as finding biomarkers to select patients that would benefit from these therapies, continues to be a major focus of research in this area. Two main mechanisms of resistance to anti-angiogenic therapy have been proposed: an intrinsic resistance to the specific therapeutic target, or an adaptive resistance in which the tumor gradually acquires the ability to evade the effects of angiogenic inhibition2. In this issue, a new study by Frentzas et al.3 offers evidence for an association between vessel co-option and resistance to the anti-angiogenic drug bevacizumab, a monoclonal antibody that inhibits VEGFA, in patients with liver metastases.

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Figure 1: Potential strategies for overcoming resistance to anti-VEGFA therapy.

Katie Vicari/Nature Publishing Group

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Authors and Affiliations

  1. Kyrre E. Emblem is in the Department of Diagnostic Physics, The Intervention Centre, Oslo University Hospital, Oslo, Norway.,

    Kyrre E Emblem

  2. Department of Radiation Oncology, Rakesh K. Jain is at the Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,

    Rakesh K Jain

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  1. Kyrre E Emblem
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  2. Rakesh K Jain
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Correspondence to Kyrre E Emblem.

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Competing interests

K.E.E. has no conflicts of interest. E.K.J. has received consultant fees from Enlight, Ophthotech, SPARC and SynDevRx, owns equity in Enlight, Ophthotech, SynDevRx and XTuit, and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. No funding or reagents from these companies were used in this study.

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Emblem, K., Jain, R. Improving treatment of liver metastases by targeting nonangiogenic mechanisms. Nat Med 22, 1209–1210 (2016). https://doi.org/10.1038/nm.4228

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