TY - JOUR T1 - The Angiopoietin-Tie2 Pathway Is a Potential Therapeutic Target in Urothelial Carcinoma JF - Anticancer Research JO - Anticancer Res SP - 3377 LP - 3382 VL - 34 IS - 7 AU - WEIGUO JIAN AU - JONATHAN M. LEVITT AU - SETH P. LERNER AU - GURU SONPAVDE Y1 - 2014/07/01 UR - http://ar.iiarjournals.org/content/34/7/3377.abstract N2 - Background: Angiopoietin/Tyrosine Kinase-2 (ANG/TIE2), Fibroblast Growth Factor-1 (FGFR1) and Vascular Endothelial Growth Factor Receptors (VEGFRs) promote growth of urothelial carcinoma (UC). We examined the pre-clinical activity of CEP-11981, a tyrosine kinase inhibitor of TIE2, FGFR1 and VEGFR-1-3, in UC. Materials and Methods: The in vitro activity of CEP-11981 was evaluated in four human UC cell lines. The effect of daily oral CEP-11981 was examined in RT4 xenografts, which also underwent immunohistochemistry (IHC) for cleaved caspase-3, Cluster of Differentiation (CD)-31, VEGFR2 and TIE2. Results: In vitro activity was not detected. Preliminary in vivo experiments suggested that CEP-11981 at both 5 mg/kg and 10 mg/kg induced similar regression of xenografts, greater than those at 2.5 mg/kg daily. Given the lower toxicity at 5 mg/kg, we performed a confirmatory experiment with 5 mg/kg, which significantly inhibited xenografts compared to controls (p<0.05). IHC of xenografts demonstrated no differences in CD31, cleaved caspase-3 or VEGFR2, but TIE2 was significantly down-regulated (p=0.008) by CEP-11981. Conclusion: CEP-11981 demonstrated a significant pre-clinical activity against human UC xenografts, which was attributable primarily to effects on TIE2 receptor. ER -