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: Eurekalert
