Abstract
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. 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. 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 Tyr(1054/1059), 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. This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.
Highlights
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%
High expression of angiogenic factors Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), and insulin-like growth factor (IGF)-2 is detected in 2 patients with HCC (14 – 17), and when released from tumor cells, inflammatory cells, and/or tumor stromal cells, they participate in the neovascularization and metastatic potential of HCC (18 – 20)
To address the mechanism by which brivanib inhibits tumor growth, we evaluated the effect of brivanib on the phosphorylation levels of VEGF receptor (VEGFR)-2 and FGF receptor (FGFR)-1, and their downstream signaling pathways, ERK1/2 and Akt, in SK-HEP1 cells and HepG-2 cells
Summary
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%. 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. BMS-540215 has been shown to selectively inhibit the proliferation of endothelial cells stimulated by VEGF and FGF in vitro with IC50 values of 40 and 276 nmol/L, respectively [13]. It shows broad-spectrum in vivo antitumor activity over multiple dose levels and induces stasis in large tumors, suggesting that it may have a role in the treatment of HCC. Because VEGFRs and FGFRs are both present on endothelial cells and provide critical signaling pathways for HCC metastasis, the use of brivanib that inhibits both VEGFR and FGFR could be of therapeutic importance
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