) The goal of this proposal are to utilize a novel technology, random peptide phage display, to identify and characterize peptides that differentiate phases of progression of prostate neoplasia by identifying molecular alterations in tissues. In the developmental phase (R21) of these studies, the technology will be advanced for use in identification of peptides that differentiate benign from malignant tissues, using human prostate cancer as a model system. To do this, new affinity selection procedures will be developed. To detect peptide-bearing phage particles when bound to both formalin-fixed, paraffin-embedded, and fresh tissues, novel histochemical techniques will be defined. The identified phage will be tested on a large series of human prostate cancer cases to confirm binding specificity and reproducibility in histochemical studies. The developed methodologies and first generation phage reagents will then be utilized in a pilot application (R33 phase) in which phage will be identified that bind to and discriminate between the precursor of prostate cancer (prostatic intraepithelial neoplasia) and prostate cancer, on the one hand, and organ-confined prostate cancer and metastatic cancer on the other. The identified phage bearing specific peptides from these experiments will be tested in well-defined clinicopathologic studies on a large series of cases to assess their value as predictors of disease progression (from pre-cancer to cancer, and from cancer to metastatic disease). Important correlations will be made with clinical and pathologic data that will be available on each of the cases used in these studies. The techniques and reagents developed in these studies may have broad applications in basic studies of prostate cancer biology by providing tools to characterize structures that differentiate the phases of cancer progression. Moreover, these studies will yield tools that will be highly useful clinically with direct applications in the field of diagnostic pathology, and may have implications for the management of prostate cancer patients.
