Effects of dual targeting of tumor cells and stroma in human glioblastoma xenografts with a tyrosine kinase inhibitor against c-MET and VEGFR2

PLoS One. 2013;8(3):e58262. doi: 10.1371/journal.pone.0058262. Epub 2013 Mar 4.

Abstract

Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In in vitro cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited in vitro. Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from in vitro experiments, in vivo blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be needed for full activity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology*
  • Animals
  • Drug Delivery Systems
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / physiology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Pyridines / pharmacology*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

  • Anilides
  • Pyridines
  • cabozantinib
  • Proto-Oncogene Proteins c-met
  • Vascular Endothelial Growth Factor Receptor-2

Grant support

The MR research in this study was made possible by investment grants NWO middelgroot 40-00506-90-0602 and NWO BIG (VISTA). ACN is supported by a grant from the Radboud University Nijmegen Medical Centre, WPJL is supported by the Dutch Brain Foundation (grant KS2010(1)-01). Computed image analysis was supported by a grant from the Maurits and Anna de Cock foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.