Abstract LB-364: Dovitinib (TKI258), a multikinase inhibitor of FGFR, PDGFR, and VEGFR tyrosine kinases, induces growth suppression in mouse models of human hepatocellular carcinoma (HCC)

Abstract

Abstract Background: Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their receptors are over-expressed and involved in the neovascularization, invasiveness, and metastatic potential of HCC. Therefore, suppression of the VEGFR/FGFR/PDGFR by TKI258 may represent a novel approach for treatment of HCC. The aims of this study were 1) to determine the in vivo antineoplastic activity of dovitinib (TKI258), a multikinase inhibitor of FGF, VEGF, and PDGF signaling pathways, and 2) to compare the efficacy of TKI258 with sorafenib in mouse models of human HCC. Experimental Design: We treated six patient-derived HCC xenografts with i) 50 or 75 mg/kg TKI258 and ii) 50 mg/kg sorafenib. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to FGF/VEGF/PDGF signaling pathways. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry. Results: Body weight was maintained up to 75 mg/kg TKI258 and 50 mg/kg sorafenib. TKI258 treatment resulted in suppression of tumor growth in a dose-dependent manner. Potent antitumor activity was observed in all six HCC xenograft lines studied. The T/C ratio's for 50 mg/kg TKI258 and 50 mg/kg sorafenib for xenograft lines 06-0606, 26-0808A, 26-1004, 28-1108, 5-1318, and 25-0705A, were 0.04 and 0.22; 0.11 and 0.18; 0.13 and 0.26; 0.23 and 0.37; 0.14 and 0.30, and 0.28 and 0.19, respectively, suggesting that in general the antitumor effect of TKI258 was greater than that of sorafenib. TKI258-induced growth inhibition was associated with inhibition of angiogenesis and cell proliferation and induction of tumor cell death. Inhibition of p-FGFR, p-PDGFR, p-VEGFR-2, p-ERK1/2, and upregulation of Bim and p-histone H2A-X Ser139 were observed. Conclusion: TKI258 demonstrated significant antitumor effect in a mouse model of human HCC xenograft. This study provides a strong rationale for clinical investigation of TKI258 in patients with HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-364.