Inhibition of functional osteoblasts with the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (PCa)

Abstract

4625 Background: In a clinical trial in men with PCa and bone metastases (Proc Am Soc Clin Oncol 2003; 22:410), monotherapy with the PDGFR inhibitor, imatinib mesylate, for 30 days, led to decreases in alkaline phosphatase (AlkP), but not a significant decline in PSA. Nevertheless, patients with any decrease in AlkP had a higher likelihood of subsequent 50% decline in PSA with subsequent combination imatinib and docetaxel therapy, as compared to patients with any increase in AlkP. Goals: To investigate whether 1) Osteoblast (OB) proliferation in PCa is regulated by PDGF and 2) effective inhibition of OBs results in enhanced therapeutic efficacy with cytotoxic therapy in PCa. Methods: 1) PDGFR immunohistochemistry in bone marrow biopsies from PCa bone metastases 2) In a co-culture model of MDA-PCa2b cells and OBs, which results in induction of OB proliferation, the effects of imatinib, alone and in combination with docetaxel therapy were studied. Results: OBs from PCa bone metastases stain positively for P...