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

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.

Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity

“…Foretinib (GSK1363089), a multikinase inhibitor of MET and VEGFRs, shows different sensitivities that are dependent on FGFR expression (22). The FGFR inhibitor that has been most extensively studied in patients with HCC is brivanib, an ATP-competitive dual inhibitor of VEGFR and FGFR1-3 (24). Despite strong preclinical and phase II data of HCC (25,26), brivanib failed in large randomized phase III trials in both the first-and second-line settings for patients with advanced HCC (27,28).…”

A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models

“…Therefore, these results suggest that LY2874455 inhibits FGFR in the cell and that its antiproliferative effects are directly linked to the inhibition of FGFR signaling. Several reported FGFR inhibitors have a dominant activity against VEGFR2 as compared with FGFRs (29)(30)(31). At efficacious doses, these molecules also retain many of the class effects associated with VEGFR2/VEGFR blockade including hypertension and bleeding (34)(35)(36)(37).…”

“…[29][30][31]. VEGF/VEGFR2-based antiangiogenic therapies are approved for the treatment of several types of cancers (26,32,33).…”

Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study

“…26 However, the eff ect of FGFR2 inhibition in that study is not clear because only three patients had FGFR2 mutations. 13,27 In another phase 2 study of single-agent nintedanib (an inhibitor of VEGF, platelet-derived growth factor, and FGF receptors that has a similar half maximal inhibitory concentration against FGFR2 as has dovitinib) 28 9·4% of patients with recurrent or persistent, previously treated endometrial cancer achieved an overall response, and the progression-free survival rate at 6 months was 21·9%. 29 However, tissue specimens were not collected and FGFR2 status of patients was not known.…”