Targeting angiopoietin-2 signaling in cancer therapy

Expert Opin Investig Drugs. 2013 Jul;22(7):813-25. doi: 10.1517/13543784.2013.793306. Epub 2013 Apr 27.

Abstract

Introduction: Over the past decade, several anti-angiogenic strategies have been devised to target a wide spectrum of malignancies. The most widely utilized approach involves abrogation of vascular endothelial growth factor receptor signaling through either consumption of ligand (i.e., with the monoclonal antibody bevacizumab) or through direct inhibition of the receptor tyrosine kinase domain (i.e., with small molecules such as sunitinib or sorafenib). While these agents do appear to delay cancer progression in the clinic, they are not curative approaches.

Areas covered: A novel anti-angiogenic strategy involves inhibition of signaling along the Ang/Tie-2 axis, a pathway critical for mediating endothelial and perivascular cell interactions. While several agents (i.e., AMG-386 and regorafenib) have reached late stages of clinical development, others (i.e., ARRY614 and CEP-11981) are in their relative infancy. Herein, we will outline the clinical trajectory of wide spectrum Ang/Tie-2 inhibitors, with attention to data evaluating combinations with cytotoxic therapy or other targeted agents.

Expert opinion: Provided that these approaches to not drastically augment toxicity, they may represent the ideal path for further development of this class of agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use*
  • Angiopoietin-2 / antagonists & inhibitors*
  • Angiopoietin-2 / metabolism
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use
  • Clinical Trials as Topic
  • Humans
  • Molecular Targeted Therapy / methods*
  • Neoplasms / blood supply
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / prevention & control*
  • Protein Binding
  • Receptor, TIE-2 / antagonists & inhibitors
  • Receptor, TIE-2 / metabolism
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / adverse effects
  • Recombinant Fusion Proteins / therapeutic use*
  • Signal Transduction / drug effects

Substances

  • Angiogenesis Inhibitors
  • Angiopoietin-2
  • Antibodies, Monoclonal
  • Recombinant Fusion Proteins
  • Receptor, TIE-2
  • trebananib