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

Abstract

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.

• Authors: Weon-Kyoo You, Barbara Sennino, Casey W Williamson, Beverly Falcón, Hiroya Hashizume, Li-Chin Yao, Dana T Aftab, Donald M McDonald
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 14 Pg. 4758-68 (Jul 15 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21613405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• 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

Topics

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