P3-17-11: Dovitinib (TKI258), a Dual Inhibitor of FGFR and VEGFR, Induces Tumor Growth Suppression in Xenograft Models of Primary Human Breast Cancer.

Abstract

Abstract Introduction: The objective of this study was to evaluate the efficacy of dovitinib (TKI258), a small-molecule dual inhibitor of fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) in mouse models of human breast cancer. Molecular epidemiological studies have implicated that FGFR1 and FGFR2 gene amplification plays a critical role in breast cancer tumorigenesis. FGFR1 gene amplification correlates with gene expression and is associated with poor prognosis in patients with estrogen receptor-positive (ER+) tumors. Dual FGFR/VEGFR inhibitory activities of dovitinib make it an attractive molecule for targeting breast cancer. Experimental Design: Dovitinib was evaluated in 3 primary human breast carcinoma xenograft models with different histological and molecular profiles: a triple-negative breast cancer model (HBCx-15), a HER2+ model (HBCx-5), and an ER+ model (HBCx-3). Dovitinib was administered orally at 20- and 40-mg/kg dose levels (n = 8–10/group), once daily for 21 consecutive days. Results: At a dose of 40 mg/kg, dovitinib demonstrated strong antitumor efficacy as a single agent, particularly in the ER+ HBCx-3 and the HER2+ BCx-5 tumor models (ΔT/T0 = −26.42% and ΔT/ΔC = 5.09%, respectively), whereas the response was less significant in the triple negative breast cancer HBCx-15 model (ΔT/ΔC = 31.7%). Conclusion: Dovitinib showed significant antitumor effect in human breast cancer xenograft mouse models. This study provides a strong rationale for clinical investigation of dovitinib in patients with advanced breast cancer, particularly in patients with ER+ and HER2+ disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-11.