The changing therapeutic landscape of castration-resistant prostate cancer
ABSTRACT Castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Before 2010, only docetaxel-based chemotherapy improved survival in patients with CRPC compared with mitoxantrone. Our improved understanding of the underlying biology of CRPC has heralded a new era in molecular anticancer drug development, with a myriad of novel anticancer drugs for CRPC entering the clinic. These include the novel taxane cabazitaxel, the vaccine sipuleucel-T, the CYP17 inhibitor abiraterone, the novel androgen-receptor antagonist MDV-3100 and the radioisotope alpharadin. With these developments, the management of patients with CRPC is changing. In this Review, we discuss these promising therapies along with other novel agents that are demonstrating early signs of activity in CRPC. We propose a treatment pathway for patients with CRPC and consider strategies to optimize the use of these agents, including the incorporation of predictive and intermediate end point biomarkers, such as circulating tumor cells.
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ABSTRACT: To explore the feasibility and efficacy of docetaxel plus prednisone for Chinese population with metastatic castration refractory prostate cancer (mCRPC). A total of 228 patients recruited from 15 centers were randomized to receive 10 cycles of D3P arm (docetaxel: 75 mg/m2, intravenous infusion, every three weeks; Prednisone 10mg orally given daily) or M3P arm (mitoxantrone: 12 mg/m2, intravenous infusion, every three weeks; Prednisone 10mg orally given daily). Primary end point was overall survival, and secondary end points were events progression-free survival (PFS), response rate, response duration. Quality of life (QoL) was also assessed in both treatment groups. The median overall survival was 21.88 months in D3P arm and 13.67 months in M3P arm (P = 0.0011, hazard ratio = 0.63, 95% confidence interval, 0.46-0.86). Subgroup analysis was consistent with the results of overall analysis. Events progression-free survival (pain, PSA, tumor and disease) were significantly improved in D3P arm compared with M3P arm. PSA response rate was 35.11% for patients treated by D3P arm and 19.39% for M3P arm (P = 0.0155). Pain response rate was higher in D3P arm (61.11%, P = 0.0011) than in M3P (23.08%) arm. No statistical differences were found between D3P arm and M3P arm for QoL, tumor response rate and response duration of PSA and pain. The tolerability and overall safety of D3P arm were generally comparable to that of M3P arm. Compared with M3P arm, D3P arm significantly prolonged overall survival for the Chinese patients with mCRPC and improved the response rate for PSA and pain. clinicaltrials.gov NCT00436839.PLoS ONE 01/2015; 10(1):e0117002. DOI:10.1371/journal.pone.0117002 · 3.53 Impact Factor
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ABSTRACT: The antiandrogen withdrawal syndrome (AAWS) is characterized by tumour regression and a decline in serum PSA on discontinuation of antiandrogen therapy in patients with prostate cancer. This phenomenon has been best described with the withdrawal of the nonsteroidal antiandrogens, bicalutamide and flutamide, but has also been reported with a wide range of hormonal agents. Mutations that occur in advanced prostate cancer and induce partial activation of the androgen receptor (AR) by hormonal agents have been suggested as the main causal mechanism of the AAWS. Corticosteroids, used singly or in conjunction with abiraterone, docetaxel and cabazitaxel might also be associated with the AAWS. The discovery of the Phe876Leu mutation in the AR, which is activated by enzalutamide, raises the possibility of withdrawal responses to novel hormonal agents. This Review focusses on the molecular mechanisms responsible for withdrawal responses, the role of AR mutations in the development of treatment resistance, and the evidence for the sequential use of antiandrogens in prostate cancer therapy. The implications of AR mutations for the development of novel drugs that target the AR are discussed, as are the challenges associated with redefining the utility of older treatments in the current therapeutic landscape.Nature Reviews Urology 01/2015; 12(1):37-47. DOI:10.1038/nrurol.2014.345 · 4.79 Impact Factor
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ABSTRACT: The six transmembrane protein of prostate 2 (STAMP2) is an androgen-regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage-independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target.EMBO Molecular Medicine 02/2015; DOI:10.15252/emmm.201404181 · 8.25 Impact Factor