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Progression to castration resistance is a major problem in the treatment of advanced prostate cancer and is likely to be driven by activation of several molecular pathways, including androgen receptor (AR) and cyclic AMP-dependent protein kinase A (PKA). In this study, we examined the therapeutic efficacy of a combined inhibition of the AR and the regulatory subunit type Ia (RIa) of protein kinase A with second generation antisense oligonucleotides (ODNs) in androgen-sensitive LNCaP and castration-resistant LNCaPabl tumors in vivo. We found that targeting the AR alone inhibited LNCaP, as well as LNCaPabl tumors. Combined inhibition resulted in an improved response over single targeting and even a complete tumor remission in LNCaPabl. Western blot analysis revealed that both ODNs were effective in reducing their target proteins when administered alone or in combination. In addition, treatment with the ODNs was associated with an induction of apoptosis. Our data suggest that dual targeting of the AR and PKARIa is more effective in inhibiting LNCaP and LNCaPabl tumor growth than single treatment and may give a treatment benefit, especially in castration-resistant prostate cancers. [ABSTRACT FROM AUTHOR]

ERG gene rearrangements are found in about one half of all prostate cancers. Functional analyses do not fully explain the selective pressure causing ERG rearrangement during the development of prostate cancer. To identify transcriptional changes in prostate cancer, including tumors with ERG gene rearrangements, we performed a meta-analysis on published gene expression data followed by validations on mRNA and protein levels as well as first functional investigations. Eight expression studies (n = 561) on human prostate tissues were included in the meta-analysis. Transcriptional changes between prostate cancer and non-cancerous prostate, as well as ERG rearrangement-positive (ERG+) and ERG rearrangement-negative (ERG−) prostate cancer, were analyzed. Detailed results can be accessed through an online database. We validated our meta-analysis using data from our own independent microarray study (n = 57). 84% and 49% (fold-change>2 and >1.5, respectively) of all transcriptional changes between ERG+ and ERG− prostate cancer determined by meta-analysis were verified in the validation study. Selected targets were confirmed by immunohistochemistry: NPY and PLA2G7 (up-regulated in ERG+ cancers), and AZGP1 and TFF3 (down-regulated in ERG+ cancers). First functional investigations for one of the most prominent ERG rearrangement-associated genes - neuropeptide Y (NPY) - revealed increased glucose uptake in vitro indicating the potential role of NPY in regulating cellular metabolism. In summary, we found robust population-independent transcriptional changes in prostate cancer and first signs of ERG rearrangements inducing metabolic changes in cancer cells by activating major metabolic signaling molecules like NPY. Our study indicates that metabolic changes possibly contribute to the selective pressure favoring ERG rearrangements in prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: New biomarkers are needed to improve the specificity of prostate cancer detection and characterisation of individual tumors. In a proteomics profiling approach using MALDI-MS tissue imaging on frozen tissue sections, we identified discriminating masses. Imaging analysis of cancer, non-malignant benign epithelium and stromal areas of 15 prostatectomy specimens in a test and 10 in a validation set identified characteristic m/z peaks for each tissue type, e.g. m/z 10775 for benign epithelial, m/z 6284 and m/z 6657.5 for cancer and m/z 4965 for stromal tissue. A 10-fold cross-validation analysis showed highest discriminatory ability to separate tissue types for m/z 6284 and m/z 6657.5, both overexpressed in cancer, and a multicomponent mass peak cluster at m/z 10775–10797.4 overexpressed in benign epithelial tissue. ROC AUC values for these three masses ranged from 0.85 to 0.95 in the discrimination of malignant and non-malignant tissue. To identify the underlying proteins, prostate whole tissue extract was separated by nano-HPLC and subjected to MALDI TOF/TOF analysis. Proteins in fractions containing discriminatory m/z masses were identified by MS/MS analysis and candidate marker proteins subsequently validated by immunohistochemistry (IHC). Biliverdin reductase B (BLVRB) turned out to be overexpressed in PCa tissue. Biological significance: In this study on cryosections of radical prostatectomies of prostate cancer patients, we performed a MALDI-MS tissue imaging analysis and a consecutive protein identification of significant m/z masses by nano-HPLC, MALDI TOF/TOF and MS/MS analysis. We identified BLVRB as a potential biomarker in the discrimination of PCa and benign tissue, also suggesting BVR as a feasible therapeutic target. [Copyright &y& Elsevier]