ABSTRACT
BACKGROUND: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane-estramustine-carboplatin (TEC) chemotherapy may be greatest. PATIENTS AND METHODS: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as > or = 50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram. RESULTS: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival. CONCLUSIONS: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bridged-Ring Compounds/administration & dosage , Carboplatin/administration & dosage , Castration , Prostatic Neoplasms/drug therapy , Taxoids/administration & dosage , Aged , Clinical Trials as Topic/statistics & numerical data , Humans , Male , Middle Aged , Prostatic Neoplasms/mortality , Prostatic Neoplasms/surgery , Treatment Failure , Treatment OutcomeABSTRACT
Astrocyte-elevated gene-1 (AEG-1) has been reported to be upregulated in several malignancies and play a critical role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase/AKT signaling pathway. However, the role of AEG-1 in prostate cancer (PC) has never been reported. We now show that AEG-1 is overexpressed in clinical PC tissue samples and cultured PC cells compared to benign prostatic hyperplasia tissue samples and normal prostate epithelial cells. Interestingly, AEG-1 knockdown induced cell apoptosis through upregulation of forkhead box (FOXO) 3a activity. This alteration of FOXO3a activity was dependent on reduction of AKT activity in LNCaP and PC-3 cells with high constitutive AKT activity, but not in DU145 cells with low constitutive AKT activity, although AEG-1 knockdown had no impact on phosphatase and tensin homolog expression in these cells. AEG-1 knockdown also attenuated the constitutive activity of the nuclear factor kappaB (NF-kappaB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-kappaB and AP-1-regulated genes (interleukin (IL)-6, IL-8 and matrix metalloproteinase-9) and significantly decreased cell invasion properties of PC-3 and DU145 cells. Overall, our findings suggest that aberrant AEG-1 expression plays a dominant role as a positive auto-feedback activator of AKT and as a suppressor of FOXO3a in PC cells. AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis.
