Biomarker Discovery and Mechanistic Studies of Prostate Cancer using Targeted Proteimic Approaches

Prostate cancer is a major contributor to cancer mortality in U.S. men, resulting in approximately 30,000 deaths each year. Prostate cancer mortality results trom metastasis to the bone and lymph nodes and progression from an androgen-dependent to an androgen-independent disease. No treatment for metastatic prostate cancer is available that effectively increases survival. Proteins on the celJ surface are at the frontier that directly interacts with the extracelJular environment and encounters signaling factors. Disruption of the expression of cell surface proteins and their post-translational modifications wilJ contribute to imbalance in prostate homeostasis, tumor cell detachment from the extraceJlular matrix and migration to distant sites. The current understanding of cell surface proteins is incomplete and the purpose of this project is to determine what proteins play which role in prostate cancer progression and metastasis. The long-term objective of this project is to understand the role of cell surface proteins in prostate cancer progression and metastasis. The hypothesis to be tested in this proposal is that celJ surface proteins displaying changes in abundances and/or post-translational modifications between benign and malignant prostate celJs are likely to be those that are potentially involved in tumor development. Those changes wilJ be identified by comparative studies of benign and malignant prostate ceJls using systematic and comprehensive approaches (i. e. proteomic approaches). The functional role of such changed proteins in prostate cancer progression and metastasis wiIJ be examined in detail. The preliminary proteomic studies have identified a number of ceJl surface proteins as differentially expressed between benign and malignant prostate ceJls. Their functional significance in prostate cancer will be determined using a variety of experiments proposed in Specific Aim 1. Encouraged by the initial success of the preliminary studies, we propose to perform more comprehensive analysis of additional types of prostate cells with different tumorigenic behavior. More proteins with relatively subtle changes between benign and malignant prostate ceJls are expected to be identified. This project is a blend of hypothesis-driven and discovery-driven research and will identify cell surface proteins that are critical to prostate cancer progression and metastasis. Measurement ofthe expression levels of such proteins in prostate cancer ceJls, particularly the prostate cancer patient specimens, wiJl potentialJy develop novel diagnostic/prognostic markers. Further elucidation of their functions wilJ provide invaluable insights into the molecular mechanisms by which localized prostate cancer metastasizes. Such mechanistic understanding will potentialJy open new avenues for therapeutic intervention of prostate cancer. This project will generate new knowledge of molecular mechanisms involved in prostate cancer as weJl as provide strong translational significance for the diagnosis and treatment of prostate cancer. The results of this project thus wilJ have direct beneficial impacts on the prostate cancer patients.