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Targeting MET and Vascular Endothelial Growth Factor Receptor Signaling in Castration-Resistant Prostate Cancer

Lee, Richard J. MD, PhD; Smith, Matthew R. MD, PhD

doi: 10.1097/PPO.0b013e318281e280

Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and vascular endothelial growth factor receptor (VEGFR) are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and VEGFR-2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date.

From the Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.

This study was supported by the Department of Defense Prostate Cancer Research Program under Award W81XWH-09-1-0471 and a Conquer Cancer Foundation Career Development Award (to R.J.L.), by National Institutes of Health Midcareer Investigator Award (no. 5K24CA121990 to M.R.S.), and competitive research awards from the Prostate Cancer Foundation.

Conflicts of Interest and Source of Funding: R.J.L. has received sponsored research funding from Exelixis, Inc, South San Francisco, CA. M.R.S. is a paid consultant of, and has received sponsored research funding from, Exelixis, Inc, South San Francisco, CA.

Reprints: Richard J. Lee, MD, PhD, Massachusetts General Hospital Cancer Center, 55 Fruit St, Yawkey 7108, Boston, MA 02114. E-mail:

© 2013 Lippincott Williams & Wilkins, Inc.