Imatinib and prostate cancer: lessons learned from targeting the platelet-derived growth factor receptor.

INTRODUCTION: The platelet derived growth factor (PDGF) signaling pathway has been implicated in both epithelial and stromal mechanisms of prostate cancer progression and postulated as a target for therapy in bone metastases. Imatinib mesylate is a potent inhibitor of the platelet-derived growth factor receptor (PDGFR) and its activity has been tested in preclinical models and in Phase I and II clinical trials. AREAS COVERED: This review summarizes the preclinical data on PDGF/PDGFR in prostate cancer, and reviews the clinical and correlative data using imatinib as a PDGFR inhibitor. EXPERT OPINION: To date, the use of imatinib to treat men with prostate cancer has been ineffective, and PDGFR inhibition may in fact accelerate advanced forms of the disease and antagonize taxane efficacy. Given the major discordance between preclinical models and clinical experimentation, an accurate understanding of the PDGF-regulated interactions between metastatic prostate cancer and the bone micro-environment is evidently warranted. Correlations of pharmacodynamic monitoring of imatinib-induced PDGFR inhibition with progression-free and overall survival outcomes have led to the hypothesis that PDGF may function as a homeostatic factor in bone metastases. Recent laboratory studies defining PDGFR-regulated pericytes as gatekeepers of metastases may relate to these clinical observations.