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

Weiguo Jian1, Jonathan M Levitt2, Seth P Lerner1

  • 1Department of Urology, Baylor College of Medicine, Houston, TX, U.S.A.

Anticancer Research
|July 2, 2014
PubMed
Abstract

Insights

CEP-11981, a tyrosine kinase inhibitor, showed significant pre-clinical activity against urothelial carcinoma (UC) xenografts. Its efficacy in UC models was primarily linked to down-regulation of the TIE2 receptor.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Urothelial carcinoma (UC) growth is promoted by Angiopoietin/Tyrosine Kinase-2 (ANG/TIE2), Fibroblast Growth Factor-1 (FGFR1), and Vascular Endothelial Growth Factor Receptors (VEGFRs).
  • CEP-11981 is a novel tyrosine kinase inhibitor targeting TIE2, FGFR1, and VEGFRs.

Purpose of the Study:

  • To evaluate the pre-clinical efficacy of CEP-11981 in urothelial carcinoma (UC).

Main Methods:

  • In vitro activity of CEP-11981 was assessed in four human UC cell lines.
  • In vivo efficacy was studied using RT4 xenografts treated with daily oral CEP-11981.
  • Immunohistochemistry (IHC) was performed on xenografts to analyze cleaved caspase-3, CD-31, VEGFR2, and TIE2 expression.

Main Results:

  • CEP-11981 demonstrated no in vitro activity against UC cell lines.
  • In vivo, CEP-11981 significantly inhibited xenograft growth at 5 mg/kg and 10 mg/kg compared to 2.5 mg/kg.
  • Immunohistochemistry revealed significant down-regulation of TIE2 in xenografts treated with CEP-11981, with no significant changes in CD31, cleaved caspase-3, or VEGFR2.

Conclusions:

  • CEP-11981 exhibits significant pre-clinical anti-tumor activity in human urothelial carcinoma xenografts.
  • The anti-cancer effects of CEP-11981 in UC are primarily mediated through its inhibition of the TIE2 receptor.
Keywords:
CEP11981FGFRUrothelial carcinomaVEGFRangiopoietin/TIE2tyrosine kinase inhibitor

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