American Association for Cancer Research

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Combined Inhibition of VEGF and c-MET Can Decrease Metastasis


February 24, 2012

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  • Inhibition of VEGF increased c-MET expression in tumors.
  • Invasion and metastasis were blocked by inhibition of VEGF plus c-MET.
  • Dual VEGF/c-MET inhibitors are in late-stage clinical trials.
PHILADELPHIA — 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.

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About the AACR

Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR’s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.  

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Media Contact:
Jeremy Moore
(215) 446-7109
Jeremy.Moore@aacr.org