Preclinical Rationale and Results

Cabozantinib is a potent, first-in-class, tyrosine kinase inhibitor that targets the MET and VEGF signaling pathways. Cabozantinib’s coordinated inhibition of the MET and VEGFR2 targets appears to effectively block the MET-driven escape seen with other targeted therapies. In preclinical studies, cabozantinib induces extensive apoptosis of malignant cells, causes tumor regression, and prevents tumor invasion.1

MET—an important escape pathway in cancer

  • MET is upregulated in a wide range of malignancies, including thyroid, prostate, ovarian, lung and breast cancers1-5
  • MET drives more invasive and aggressive behavior of tumor cells, resulting in metastasis5,7
  • MET is further upregulated by the hypoxic conditions created by VEGF pathway inhibitors, which leads to promotion of metastasis5,7
  • Blocking VEGF alone can have immediate antiangiogenic and anti-tumor effects, but over the longer term it may enable cancer progression, tumor invasion, and metastasis1,7
  • Targeting the MET and VEGF pathways simultaneously disrupts metastasis and angiogenesis1,8

 

References:

  1. Yakes, F. M., et. al.  2011 Draft Manscript.  Data on file.  Exelixis, Inc.
  2. Danilkovitch-Miagkova, A., et. al.  2001.  J. Clin. Invest.
  3. Christensen, J.G., et. al. 2005.  Cancer Letters.
  4. Capdevila, J. et. al.  2010.  Discov. Med.
  5. Eder, J.P., et. al.  2009.  Clin. Cancer Res.
  6. Pennacchietti, S., et. al.  2003.  Cancer Cell.
  7. Bergers, G., et. al.  2008.  Nat. Rev. Cancer.
  8. Smith, D.C., et. al.  2011 (suppl).  J. Clin Oncol.