Dovitinib (Tki258), A Dual Inhibitor Of Fgfr And Vegfr, Induces Tumor Growth Suppression In Xenograft Models Of Human Bladder Cancer

Introduction: The aim 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 bladder cancer. Molecular epidemiological studies have implicated FGFR and VEGFR pathways in the pathogenesis of high grade, muscle invasive bladder cancer. Somatic activating mutations in FGFR3 have been identified in 16%-20% of muscle-invasive bladder cancer and FGFR3 overexpression has also been documented in a high fraction of bladder cancers. High microvessel density, serum VEGF levels and urine FGF2 levels have also been associated with high grade bladder cancer and poor disease-free survival. Dual FGFR/VEGFR inhibitory activities of dovitinib make it an attractive molecule targeting advanced bladder cancer. Experimental Design: Dovitinib was evaluated in the RT112 human bladder carcinoma xenograft model. Dovitinib was administered orally at three dose levels (n = 10/group), once daily for 28 consecutive days (qd × 28). A rat RT112 xenograft study was also carried out to evaluate the PK/PD effect of single dose dovitinib administration. Results: Dovitinib at 15, 30, and 60 mg/kg resulted in tumor growth suppression, with mean changes of 60% T/C, 6% T/C (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3575. doi:10.1158/1538-7445.AM2011-3575