VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer

Cancer Res. 2011 Jul 15;71(14):4758-68. doi: 10.1158/0008-5472.CAN-10-2527. Epub 2011 May 25.


Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis.

Publication types

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

MeSH terms

  • Adenoma, Islet Cell / blood supply*
  • Adenoma, Islet Cell / drug therapy*
  • Adenoma, Islet Cell / pathology
  • Anilides / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Basement Membrane / drug effects
  • Basement Membrane / metabolism
  • Basement Membrane / pathology
  • Cell Hypoxia / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Pancreatic Neoplasms / blood supply*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridines / pharmacology
  • Quinolines / pharmacology
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
  • Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-3 / biosynthesis


  • Anilides
  • GSK 1363089
  • Pyridines
  • Quinolines
  • Vascular Endothelial Growth Factor A
  • cabozantinib
  • Proto-Oncogene Proteins c-met
  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-3