Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma

J Neurooncol. 2015 Jan;121(1):91-100. doi: 10.1007/s11060-014-1612-1. Epub 2014 Sep 12.

Abstract

Anti-angiogenic therapy is a promising therapeutic strategy for the highly vascular and malignant brain tumor, glioblastoma (GBM), although current clinical trials have failed to demonstrate an extension in overall survival. The small molecule tyrosine kinase inhibitor axitinib that targets vascular endothelial growth factor receptor, potently inhibits angiogenesis and has single-agent clinical activity in non-small cell lung, thyroid, and advanced renal cell cancer. Here we show that axitinib exerts direct cytotoxic activity against a number of patient-derived GBM stem cell (GSCs) and an endothelial cell line, and inhibits endothelial tube formation in vitro. Axitinib treatment of mice bearing hypervascular intracranial tumors generated from human U87 glioma cells, MGG4 GSCs and mouse 005 GSCs significantly extended survival that was associated with decreases in tumor-associated vascularity. We thus show for the first time the anti-angiogenic effect and survival prolongation provided by systemic single agent treatment with axitinib in preclinical orthotopic GBM models including clinically relevant GSC models. These results support further investigation of axitinib as an anti-angiogenic agent for GBM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Axitinib
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / physiopathology
  • Cell Line, Tumor
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / physiopathology
  • Humans
  • Imidazoles / pharmacology*
  • Indazoles / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / physiology
  • Neovascularization, Pathologic / drug therapy
  • Protein Kinase Inhibitors / pharmacology
  • Random Allocation
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Survival Analysis

Substances

  • Angiogenesis Inhibitors
  • Imidazoles
  • Indazoles
  • Protein Kinase Inhibitors
  • Axitinib
  • Receptors, Vascular Endothelial Growth Factor