Polycomb-mediated silencing in neuroendocrine prostate cancer

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa) for which the median survival remains less than a year. Current treatments are only palliative in nature, and the lack of suitable pre-clinical models has hampered previous efforts to develop novel therapeutic strategies. Addressing this need, we have recently established the first in vivo model of complete neuroendocrine transdifferentiation using patient-derived xenografts. Few genetic differences were observed between parental PCa and relapsed NEPC, suggesting that NEPC likely results from alterations that are epigenetic in nature. Thus, we sought to identify targetable epigenetic regulators whose expression was elevated in NEPC using genome-wide profiling of patient-derived xenografts and clinical samples. RESULTS: Our data indicate that multiple members of the polycomb group (PcG) family of transcriptional repressors were selectively upregulated in NEPC. Notably, CBX2 and EZH2 were consistently the most highly overexpressed epigenetic regulators across multiple datasets from clinical and xenograft tumor tissues. Given the striking upregulation of PcG genes and other transcriptional repressors, we derived a 185-gene list termed 'neuroendocrine-associated repression signature' (NEARS) by overlapping transcripts downregulated across multiple in vivo NEPC models. In line with the striking upregulation of PcG family members, NEARS was preferentially enriched with PcG target genes, suggesting a driving role for PcG silencing in NEPC. Importantly, NEARS was significantly associated with high-grade tumors, metastatic progression, and poor outcome in multiple clinical datasets, consistent with extensive literature linking PcG genes and aggressive disease progression. CONCLUSIONS: We have explored the epigenetic landscape of NEPC and provided evidence of increased PcG-mediated silencing associated with aberrant transcriptional regulation of key differentiation genes. Our results position CBX2 and EZH2 as potential therapeutic targets in NEPC, providing opportunities to explore novel strategies aimed at reversing epigenetic alterations driving this lethal disease

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Retrospective, observational, multicentre study on an Italian population affected by chronic hepatitis C who failed to clear HCV-RNA after the combined therapy (PEG-IFN and ribavirin): NADIR study.

There is a lack of information on the characteristics of patients with chronic hepatitis C virus infection (HCV) who fail to respond to antiviral treatment. We studied HCV-positive subjects with chronic liver diseases treated with pegylated-interferon (PEG-IFN) and ribavirin (RBV) who failed to clear HCV in routine clinical practice. A total of 2150 consecutive adult patients treated with PEG-IFN plus RBV therapy in 46 Italian centres between 1 July 2004, and 30 June 2005, were studied. Of the 2150 patients, 923 (42.9%) (M/F 585/335, mean age 54.8 years) failed to achieve a serum HCV-RNA clearance. Of these 923 patients, 429 (46.5%) were nonresponders, 298 (32.3%) relapsers, 168 (18.2%) drop-outs for noncompliance or adverse events and 28 (3.0%) were lost during follow-up. Overall, 642 (70.6%) patients received adequate therapy (defined as more than 80% of the drug doses for >80% of the time). Genotypes 1-4 were observed in 76.9% of cases; genotypes 2-3 in 21.2% and mixed in 1.9%, respectively. Multiple logistic regression analysis identified genotypes 1 and 4 as the sole independent predictors of the likelihood of nonresponse to therapy compared with relapse (OR: 4.38; 95% CI = 2.28-8.4). Age older than 65 years was the sole independent factor associated with no adherence to therapy (OR: 2.22; 95% CI = 1.36-3.62). Patients who fail to respond to treatment are a nonhomogeneous population with different features, and the sole factor that discriminates nonresponse from relapse is the distribution of genotypes 1-4. Co-morbidities are unable to determine the type of treatment failure and inadequate adherence to therapy mostly affects patients older than 65 years of age