Proteomic Predictors of Clinical Outcome of Targeted Therapies in Prostate Cancer

Stanford University, Stanford CA

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Abstract

The lack of biomarkers for assessment of which patients may respond to pathway-targeted therapy creates a[unreadable] profound need for the application of integrated technologies for the discovery and translational validation of[unreadable] such biomarkers. Recent advances in proteomic methods and computational bioinformatics processing have[unreadable] enabled application of integrated proteomic technologies to the discovery of biomarkers. If used by ex vivo[unreadable] nano-sensor devices and in vivo nanoparticle imaging methods such biomarkers may provide effective new[unreadable] tools to cancer therapy development and use. We propose to discover candidate markers by integrating two[unreadable] directed and two comprehensive proteomic technologies: a) intracellular-signaling protein chips consisting of[unreadable] a directed analysis method which quantitates known, intracellular signaling proteins; b) living-cell capture[unreadable] sensor arrays which represent a nanosensor approach for directed analysis of the cell-surface and secretory[unreadable] proteomes; c) biotin-capture-based cell-surface profiling methods consisting of a comprehensive analysis[unreadable] method that identifies and quantitates the abundance of cell-surface proteins; d) solid-phase extraction of[unreadable] glycoprotein (SPEG) profiling, which is a comprehensive analysis method for the study of secreted proteins[unreadable] and blood. Biomarker discovery will initially be disease- (prostate cancer) and pathway- (human epidermal[unreadable] growth factor receptor (Her)-kinase axis) focused and will provide a foundation our CCNE-TR Center will use[unreadable] to produce, evaluate and validate nanosensors and nanoparticle-based imaging. We will first define the cell-surface[unreadable] and secretory proteomes of androgen-independent prostate cancer and identify proteins within these[unreadable] and the intracellular proteome that are indicative of the perturbations to the Her-kinase axis. We will analyze[unreadable] these sub-proteomes in primary culture models of androgen-independent prostate cancer by treatment with[unreadable] the Her-kinase targeted therapeutics, 2C4 (a humanized monoclonal antibody that binds epitopes on Her-2[unreadable] that prevent ligand-mediated Her-2 heterodimerization) and geftinib (a small molecule inhibitor that competes[unreadable] for the ATP binding site on epidermal growth factor receptor). We will additionally stimulate with ligands[unreadable] targeting each of the receptor-dimer partners of this axis. Axis-response-informative proteins will be[unreadable] evaluated for their Her-kinase and prostate cancer specificity, by comparison with a database of gene and[unreadable] protein expression in other cell lines of different tissue origin available to the investigator group. Next we will[unreadable] integrate our in vitro results with information of the protein expression patterns of human xenograft models to[unreadable] identify a panel of markers with utility for predicting and/or for monitoring response. The bank of blood and[unreadable] viable tissue samples developed by the UCLA Prostate SPORE for use in this project represent different pre[unreadable] and post-treatment time points and a diverse collection of androgen-independent xenograft models[unreadable] characterized for sensitivity to the Her-kinase-targeted therapeutics. Lastly we will validate the utility of the[unreadable] biomarkers discovered in Specific Aims 1 and 2 for use with ex vivo nanosensor devices and in vivo[unreadable] nanoparticle imaging by generating affinity reagents for protein candidates; We will also validate the panel's[unreadable] ability to guiding human therapeutic intervention by using SPORE tissue and serum samples of prostate[unreadable] cancer patients treated with Her-kinase-directed therapies.