Combined inhibition of c-Met and VEGF suppresses tumour invasion and metastasis in pancreatic neuroendocrine tumours
Dual VEGF/c-MET inhibitors are in late-stage clinical trials
- Date : 01 Mar 2012
- Topic : Gastrointestinal cancers
Dual inhibition of vascular endothelial growth factor (VEGF) and c-MET signalling inhibited tumour invasion and metastasis in a laboratory model of pancreatic neuroendocrine cancer, according to a paper published in Cancer Discovery. The study is the first to show how the drug combination works in the laboratory.
Inhibition of VEGF increased c-MET expression in tumours
Previous laboratory research had shown that inhibition of VEGF signalling with agents like bevacizumab or sunitinib can increase tumour invasion and metastasis.
What was not known is whether anti-VEGF therapy results in elevated c-MET expression, which has been previously shown to promote tumour cell invasiveness and metastasis. To determine this, researchers led by Dr Donald McDonald, a professor at the University of California San Francisco Comprehensive Cancer Centre, conducted a two-phase laboratory study.
Researchers treated mice engineered to develop pancreatic neuroendocrine tumours with an anti-VEGF antibody, which reduced tumour size but increased invasiveness and metastasis. This treatment also increased tumour hypoxia and expression and activity of c-MET.
Invasion and metastasis blocked by inhibition of VEGF plus c-MET
When both VEGF and c-MET signaling were inhibited simultaneously, researchers observed a reduction in invasion and metastasis. They tested three c-MET inhibitors: crizotinib and PF-04217903, which target c-MET but not VEGF signalling, and cabozantinib, a dual inhibitor that blocks VEGF and c-MET signalling.
Researchers conducted their initial study in neuroendocrine pancreatic tumours because the genetic mouse model of these tumours has been studied so extensively, and then observed the effect in other tumours as well.
Two-target approach may have a broad application for treating a wide variety of cancers
This work may improve the effectiveness of combination treatments that include drugs like bevacizumab. The drugs used in the tests belong to classes of pharmaceuticals that are either on the market or under development in clinical trials. Clinical trials are already underway to gauge effectiveness of the approach in humans with prostate cancer, breast cancer, and other tumour types.
This study is the first to show how the drug combination works in the laboratory. These promising laboratory results still need more tests of safety and effectiveness in the clinic. The intent of the study was to explore a mechanism, and at the moment there is no indication that this effect will be confined to pancreatic tumours.
None of the authors from academia has any financial interest in the companies that make the drugs used in the experiments, which also involved scientists at Pfizer and Exelixis. The work was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, both components of the National Institutes of Health. Additional support was provided by the companies Pfizer and Exelixis and by AngelWorks Foundation.
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