The angiopoietin-TIE2 pathway is a potential therapeutic target in urothelial carcinoma

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/KDR/Flk-1 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/KDR/Flk-1, 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.

CEP11981; FGFR; Urothelial carcinoma; VEGFR; angiopoietin/TIE2; tyrosine kinase inhibitor.