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Circulating vascular endothelial growth factor receptor 2/pAkt-positive cells as a functional pharmacodynamic marker in metastatic colorectal cancers treated with antiangiogenic agent

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Summary

Objective

The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has received considerable attention as a first-line treatment of advanced colorectal cancers. Difficulties associated with effectively monitoring the activity of this drug have prompted us to seek a pharmacodynamic marker suitable for defining the optimum biological dose and schedule of bevacizumab administration against colon cancer in early clinical trials.

Methods

We evaluated inhibitory effects of bevacizumab on VEGF signaling and tumor growth in vitro and in vivo, and assessed phosphorylation of VEGF receptor 2 (VEGFR2) and downstream signaling in endothelial cells as pharmacodynamic markers using phospho-flow cytometry. We also validated markers in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy.

Results

In in vitro studies, bevacizumab inhibited proliferation of human umbilical vein endothelial cells in association with reduced VEGF signaling. Notably, bevacizumab inhibited VEGF-induced phosphorylation of VEGFR-2, Akt, and extracellular signal-regulated kinase (ERK). In vivo, treatment with bevacizumab inhibited growth of xenografted tumors and attenuated VEGF-induced phosphorylation of Akt and ERK. The median percentages of VEGFR2 + pAkt + and VEGFR2 + pERK + cells, determined by phospho-flow cytometry, were approximately 3-fold higher in mCRC patients than in healthy controls. Bevacizumab treatment decreased VEGFR2 + pAkt + cells in 18 of 24 patients on day 3.

Conclusion

Bevacizumab combined with chemotherapy decreased the number of VEGFR2 + pAkt + cells, reflecting impaired VEGFR2 signaling. Together, these data suggest that changes in the proportion of circulating VEGFR2 + pAkt + cells may be a potential pharmacodynamic marker of the efficacy of antiangiogenic agents, and could prove valuable in determining drug dosage and administration schedule.

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Acknowledgments

This study was supported by a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A090660) and a faculty research grant of Department of Internal Medicine, Yonsei University College of Medicine for 2009.

Disclosure Statement

The authors indicate no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea

    Sang Joon Shin, Joong Bae Ahn, Sun Young Rha, Jae Kyung Roh & Hyun Cheol Chung

  2. Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu, Seoul, 120-752, South Korea

    Sang Joon Shin, Jee Won Hwang, Joong Bae Ahn, Sun Young Rha, Jae Kyung Roh & Hyun Cheol Chung

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  1. Sang Joon Shin
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Correspondence to Hyun Cheol Chung.

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Shin, S.J., Hwang, J.W., Ahn, J.B. et al. Circulating vascular endothelial growth factor receptor 2/pAkt-positive cells as a functional pharmacodynamic marker in metastatic colorectal cancers treated with antiangiogenic agent. Invest New Drugs 31, 1–13 (2013). https://doi.org/10.1007/s10637-012-9817-7

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  • DOI: https://doi.org/10.1007/s10637-012-9817-7

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