Inhibition of a proteinase involved in tumor invasion

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DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth and fifth most common cause of cancer-related deaths in men and women, respectively, in the United States. Detection is normally observed only in late stages of the disease; thus, prognosis of patients upon diagnosis is extremely poor. As the only curative intervention is early surgery, with delayed detection the one-year survival rate of patients is less than 10% after the disease has been diagnosed and the 5-year survival rate is negligible. Carcinomas of the pancreas are also characterized by their aggressive invasiveness and metastasis. The process by which neoplasms metastasize is composed of a complex series of events. One of the initial steps in tumor cell invasion is the degradation of the basal lamina and local invasion of the surrounding tissue. Invasion and metastasis is thus dependent upon the action of a variety of degradative enzymes produced by the tumor cells themselves or cells of the host tissue. Consistent with this notion, increased amounts of proteinase activities in malignant tissues as compared with control tissues have been reported. We have made the novel observation that the metalloproteinase meprin is expressed in pancreatic tumors but not in normal pancreatic tissues. Meprins have been shown to degrade extracellular matrix components. Using stable cell lines generated to express recombinant meprin , we have found that expression of meprin increases the invasiveness of cells in invasion assays in vitro. Based on these observations, we hypothesize that meprin is involved in pancreatic tumor invasion and metastasis and may serve as a target for therapeutic intervention. The goal of this project, therefore, is to prepare reagents to inhibit the proteolytic activity of meprin and to examine their ability to inhibit in vitro cell invasion. The successful completion of these studies would provide further validation of these proteases as targets for therapeutic intervention for this deadly neoplasm. In this study, we propose the following specific aims: 1) to identify peptide inhibitors of meprin activity using phage display and 2) to obtain mouse monoclonal antibodies against human meprin that inhibit tumor cell invasion.