Caveolin-1 as a biomarker of Src family kinase/Abl inhibition in castrate-resistant prostate cancer.

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45 Background: Bone metastases cause significant morbidity in men with castrate-resistant prostate cancer (CRPC). Caveolin-1 (Cav-1), a Src kinase substrate, is overexpressed in primary prostate cancer (PCa) and in PCa bone metastases. In addition, PCa-derived and secreted Cav-1 contributes to malignant progression. We reasoned that Cav-1 may serve as a biomarker of dasatinib (a Src family kinase [SFK]/Abl inhibitor) activity in CRPC patients enrolled in a phase II clinical trial of docetaxel plus dasatinib. Methods: Levels of prostate-specific antigen (PSA), Cav-1, and markers of bone turnover were measured from baseline and cycle-2, day-1 samples from patients (n = 32) enrolled in this trial. Changes in these markers were stratified by response (responders [R] vs. nonresponders [NR]) and by predominant disease site (lymph node vs. bone). We evaluated Cav-1 expression in human PCa bone metastases samples from trial patients by immunohistochemistry. In parallel, Cav-1 secretion in response to dasatinib treatment was analyzed in PCa cells and osteoblasts. Results: Serum Cav-1 levels correlated directly with PSA levels in responding patients with node-positive disease (R vs. NR, p = 0.08) but correlated inversely in responding patients with bone-predominant disease (R vs. NR, p = 0.001). Serum from a separate cohort of patients treated with docetaxel only showed no effect on serum Cav-1 levels (R vs. NR, p = 0.85). Levels of Cav-1 were high in the active OBLs in bone specimens with PCa metastases, but not in bone specimens without metastases. Dasatinib treatment led to reduced secretion of Cav-1 in PC-3 and DU145 PCa cells but to increased secretion of Cav-1 in primary mouse osteoblasts or pre-osteoblast MC3T3-E1 cells. Conclusions: Our results suggest that serum Cav-1 serves as a novel discriminating biomarker for SFK/Abl inhibition in both node-positive and bone-metastatic CRPC. The expression of Cav-1 in OBLs of patients with PCa bone metastases suggests that tumor-associated OBLs are an important source of Cav-1 production in bone marrow. Our data provide evidence that the increase in serum Cav-1 in these patients with bone disease likely occurs through a direct effect of dasatinib on osteoblasts. No significant financial relationships to disclose.