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Title: Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma
Authors: Huynh, H 
Ngo, V.C
Fargnoli, J
Ayers, M
Khee, C.S
Heng, N.K
Choon, H.T
Hock, S.O
Chung, A 
Chow, P 
Pollock, P
Byron, S
Tran, E
Keywords: basic fibroblast growth factor
brivanib alaninate
caspase 3
CD31 antigen
fibroblast growth factor receptor 1
Ki 67 antigen
mitogen activated protein kinase 1
mitogen activated protein kinase 3
protein kinase B
vasculotropin receptor 2
brivanib alaninate
drug derivative
fibroblast growth factor receptor
triazine derivative
vasculotropin receptor
animal experiment
animal model
animal tissue
antiangiogenic activity
antiangiogenic therapy
antineoplastic activity
cancer inhibition
cancer model
cell proliferation
cell strain HepG2
controlled study
down regulation
drug mechanism
drug sensitivity
enzyme inhibition
human cell
human tissue
liver cell carcinoma
neovascularization (pathology)
priority journal
protein expression
protein phosphorylation
signal transduction
tumor vascularization
tumor xenograft
weight change
cancer transplantation
chemical model
drug antagonism
liver tumor
tumor cell line
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Proliferation
Liver Neoplasms
Models, Chemical
Neoplasm Transplantation
Neovascularization, Pathologic
Receptors, Fibroblast Growth Factor
Receptors, Vascular Endothelial Growth Factor
Issue Date: 2008
Citation: Huynh, H, Ngo, V.C, Fargnoli, J, Ayers, M, Khee, C.S, Heng, N.K, Choon, H.T, Hock, S.O, Chung, A, Chow, P, Pollock, P, Byron, S, Tran, E (2008). Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clinical Cancer Research 14 (19) : 6146-6153. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Purpose: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. Experimental Design: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. Results: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr1054/1059, increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. Conclusion: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC. ©2008 American Association for Cancer Research.
Source Title: Clinical Cancer Research
ISSN: 10780432
DOI: 10.1158/1078-0432.CCR-08-0509
Rights: Attribution 4.0 International
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