Cabozantinib blocks c-MET and VEGF signaling in mouse model of pancreatic cancer

Dual inhibition of vascular endothelial growth factor and c-MET signaling inhibited tumor invasion and metastasis in a laboratory model of pancreatic neuroendocrine cancer, according to a paper published in Cancer Discovery, the newest journal of the American Association for Cancer Research.

"Inhibition of VEGF signaling plus c-MET signaling results in a synergistic effect on tumors that leads to slowing of tumor growth and decreased invasiveness and metastasis," said lead researcher Donald M. McDonald, M.D., Ph.D., a professor at the University of California San Francisco Comprehensive Cancer Center.

Previous laboratory research had shown that inhibition of VEGF signaling with agents like bevacizumab or sunitinib can give rise to a number of side effects including increased tumor invasion and metastasis.

What was not known was whether anti-VEGF therapy results in elevated c-MET expression, which has been previously shown to promote tumor cell invasiveness and metastasis. To determine this, McDonald and colleagues conducted a two-phase laboratory study. They treated mice engineered to develop pancreatic neuroendocrine tumors with an anti-VEGF antibody, which reduced tumor size but increased invasiveness and metastasis. This treatment also increased tumor hypoxia and expression and activity of c-MET.

However, when both VEGF and c-MET signaling were inhibited simultaneously, there was a reduction in invasion and metastasis. The researchers tested three c-MET inhibitors: crizotinib and PF-04217903, which target c-MET but not VEGF signaling, and cabozantinib, a dual inhibitor that blocks VEGF and c-MET signaling.

McDonald said they conducted their initial study in neuroendocrine pancreatic tumors because the genetic mouse model of these tumors has been studied so extensively, and then observed the effect in other tumors as well.

"The intent of this study was to explore a mechanism, and there is no indication that this effect will be confined to pancreatic tumors," he said.

Source: American Association for Cancer Research