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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

 Sang Joon Shin  ;  Jee Won Hwang  ;  Joong Bae Ahn  ;  Sun Young Rha  ;  Jae Kyung Roh  ;  Hyun Cheol Chung 
 INVESTIGATIONAL NEW DRUGS, Vol.31(1) : 1-13, 2013 
Journal Title
Issue Date
Adult ; Aged ; Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use ; Animals ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Bevacizumab ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/metabolism* ; Colorectal Neoplasms/pathology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Human Umbilical Vein Endothelial Cells ; Humans ; Mice ; Mice, Nude ; Middle Aged ; Proto-Oncogene Proteins c-akt/metabolism* ; Tumor Burden/drug effects ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-2/metabolism* ; Xenograft Model Antitumor Assays
VEGFR2 ; Akt ; Bevacizumab ; Pharmacodynamic marker ; Phospho-flow cytometry
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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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
Yonsei Authors
Roh, Jae Kyung(노재경)
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Ahn, Joong Bae(안중배) ORCID logo https://orcid.org/0000-0001-6787-1503
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
Hwang, Jee Won(황지원)
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