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Agents that target the c-MET pathway may prove to have significant benefit when combined with inhibitors of angiogenesis.
Donald M. McDonald, MD, PhD
ProfessorDepartment of AnatomyHelen Diller Family Comprehensive Cancer CenterUniversity of CaliforniaSan Francisco
Agents that target the c-MET pathway may prove to have significant benefit when combined with inhibitors of angiogenesis, particularly vascular endothelial growth factor (VEGF) inhibitors, according to a study published in Cancer Discovery, an American Association for Cancer Research journal.
The findings suggest future implications for treatment regimens involving drugs that target VEGF, such as bevacizumab (Avastin, Genentech), which has been controversial in metastatic breast cancer. Donald M. McDonald, MD, PhD, led a research group at the University of California, San Francisco, that explored single VEGF and dual inhibition strategies in preclinical mouse models of neuroendocrine pancreatic tumors.
Their results confirmed that targeting VEGF alone led to increased invasion and metastasis. They further demonstrated that one of the potential mechanisms for this increased tumor aggressiveness was an increase in the activation of MET receptor signaling in these tumor cells.
The key finding, however, was that the subsequent addition of MET receptor inhibitors to VEGF-targeted agents blocks invasion and metastasis, as does the use of a combined inhibitor of VEGF and MET receptors.
The dual inhibition strategy turned aggressive tumors in the mice into tiny balls with few or no metastases.
“These findings do not exclude the involvement of mechanisms of evasive resistance other than upregulation of c-MET, but they do provide proof of concept that certain types of resistance that develop in response to angiogenesis inhibitors that inhibit VEGF signaling can be overcome therapeutically,” McDonald said in an e-mail interview.
Specifically, investigators examined the effects of using an anti-VEGF neutralizing antibody or sunitinib (Sutent, Pfizer), which inhibits VEGF receptors and other receptor tyrosine kinases, including platelet-derived growth factor receptor and KIT.
They tested these agents alone or in combination with the investigational MET receptor inhibitors crizotinib (PF-02341066) and PF-04217903 (both from Pfizer), in addition to testing a dual inhibitor of VEGF and MET receptors, cabozantinib (XL184, Exelixis).
“It’s the combination of approaches—there’s a synergy between the two,” McDonald said in a press release, explaining the benefits that researchers observed.
Angiogenesis, one of the six hallmarks of cancer, allows cancer cells to obtain the oxygen and nutrients necessary for sustaining their growth. Most angiogenesis inhibitors, including bevacizumab, target the VEGF ligand or its receptor. The FDA has approved bevacizumab for the treatment of metastatic colorectal cancer, advanced nonsquamous non-small cell lung cancer, metastatic kidney cancer, and glioblastoma. However, the agency revoked the drug’s indication in metastatic breast cancer in 2011 due to a lack of data showing improved survival, and the potential for serious adverse events.
Human agents investigated
Tumor-bearing RIP-Tag2 transgenic mice
A number of research groups have been investigating the reasons for poor response to antiangiogenic agents and have discovered that although they slow tumor growth, they also increase the aggressiveness of the tumor by promoting invasion and metastasis.
Further observation has revealed that treatment with agents that blocked both VEGF receptors and other receptor tyrosine kinases (including c-MET) do not have this effect, and inhibit both angiogenesis and invasion and metastasis. Given the role of c-MET in these cellular processes, researchers hypothesized that the concurrent inhibition of c-MET by these multitargeted inhibitors may be responsible for the reduction in invasiveness and metastasis.
This study suggests that activation of the MET receptor signaling is one of the mechanisms responsible for increased aggressiveness of tumors following inhibition of angiogenesis, and that concurrent targeting of the MET receptor may help to avoid this effect and achieve optimal patient outcomes. Clinical trials are already underway to test this approach in patients with various tumor types.
Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discovery. 2012; 2(3): OF1-OF18.