Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) are glycoproteins secreted by prostate epithelial cells, and have a long clinical history of use as serum biomarkers of prostate cancers. These two proteins and many other prostatic-derived proteins are present at significantly higher concentrations in seminal plasma and expressed prostatic secretions (EPS) in urine following a digital rectal exam prostate massage. New advances in mass spectrometry instrumentation and techniques have fueled a renewed emphasis on characterizing alterations in glycan structures on proteins associated with cancers. Previous published studies on a handful of samples have suggested that the presence of different N-linked glycan structures on PSA and PAP could distinguish benign prostate diseases from prostate cancer. Our preliminary data on PSA and PAP glycans derived from large seminal plasma cohorts and comparisons of individual sample spots has confirmed this. A combination of multiple mass spectrometry and ELISA- based approaches to characterizing N-linked glycans derived from PSA and PAP in prostatic fluids are proposed. This approach specifically tests the hypothesis that multiple glycan structural changes are detectable and consistently occur on secreted prostatic proteins like PSA and PAP as prostate cancers progress in disease severity. Our approach represents a paradigm shift for prostate cancer biomarker strategies away from the traditional serum or tissue based sources. It also emphasizes the development of diagnostic assays based on the well described changes in carbohydrate expression of surface and secreted glycoproteins associated with the cancer phenotype. To accomplish these goals, we have assembled a synergistic collaborative team with expertise in prostate cancer translational research and proteomics combined with glycan analysis specialists. The requisite clinical samples, instrumentation and glycan analysis workflows are available to accomplish the following specific aims. 1) Identify N-linked glycan biomarkers on PAP and PSA in proximal prostatic fluids reflective of prostate cancer pathology and disease state. 2) The detection and pre-validation of prostate-disease specific PAP and PSA glycoforms in a large-scale cohort of EPS urines obtained after digital rectal exams. Specific sialic acid and fucose targeted lectin ELISAs will be developed. 3) Identify additional candidate prostatic disease glycoprotein biomarkers in the EPS sample cohort using iTRAQ comparisons, including a comprehensive profile of the glycan changes across disease states. We expect that characterization of the glycans on PSA and PAP will identify molecular markers that improve prostate cancer detection and risk stratification.
The current strengths and limitations of the PSA serum test for early detection and treatment of prostate cancers are well documented, and it is clear new diagnostic biomarkers are needed for this disease. We propose to characterize cancer specific changes in the glycan components of proteins in fluids secreted by the prostate. Identification of these molecular markers will improve prostate cancer detection and risk stratification prior to biopsy and prostatectomy procedures.
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