title: The angiopoietin-TIE2 pathway is a potential therapeutic target in urothelial carcinoma.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  CEP-11981 demonstrated a significant pre-clinical activity against human UC xenografts, which was attributable primarily to effects on TIE2 receptor.
authors: Department of Urology, Baylor College of Medicine, Houston, TX, U.S.A.
authors: Weiguo
authors: W
authors: Jian
authors: Department of Urology, Baylor College of Medicine, Houston, TX, U.S.A. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, U.S.A.
authors: Jonathan M
authors: JM
authors: Levitt
authors: Department of Urology, Baylor College of Medicine, Houston, TX, U.S.A.
authors: Seth P
authors: SP
authors: Lerner
authors: Department of Medicine, Division of Medical Oncology, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, U.S.A. gsonpavde@uabmc.edu.
authors: Guru
authors: G
authors: Sonpavde
mesh_terms: D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C571190:11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo(5,4-a)pyrrolo(3,4-c)carbazol-4-one; D042682:Angiopoietins; D002227:Carbazoles; D007191:Indazoles; D042787:Receptor, TIE-2
keywords: CEP11981; FGFR; Urothelial carcinoma; VEGFR; angiopoietin/TIE2; tyrosine kinase inhibitor