Abstract 1769: A novel potential cancer marker and therapeutic target

In our recent research activities, we identified 89 novel candidate markers for prevalent cancers by a systematic Tissue microarray analysis (TMA) of a large collection of polyclonal antibodies (pAbs, approximately 1600) raised against membrane-associated and secreted human proteins currently marginally characterized. Monoclonal antibodies were generated towards 20 distinct antigens that are being characterized and validated for diagnostic and therapeutic applications. Among them, here we describe the molecular characterization of a novel cancer -associated protein (referred as EXN32) belonging to the metallo-protease family and so far only marginally characterized. Immuno-histochemical analysis of Tissue Microarrays carrying clinical specimens from prevalent cancers and matched normal samples with the anti-EXN32 pAb showed that the protein is over-expressed in breast, lung, ovary,and colon cancers, with frequencies ranging from 30 to 70%. A characterization of the protein biological role showed that alteration of EXN32 expression significantly hampers cell proliferation, migration and invasiveness. Initial studies aimed at identifying the molecular pathways in which the protein is involved show that it plays a role in the response to the reticular stress and hypoxia. A highly specific murine monoclonal antibody (mAb) specifically recognizes the protein in the four cancer types. This mAb is currently used to discover statistical associations between EXN32 with specific clinic-pathological parameters using high density tissue microarrays carrying highly characterized clinical specimens (300-700 per each cancer). Available data on breast and colon show that EXN32 is over-expressed in all cancer stages and grades. In breast cancer, a EXN32 bio-distribution analysis versus clinically relevant surface receptors shows that the protein is over-expressed in Her-2+, PR+ and ER+ patients and also in triple negative cases. In colon cancer, EXN32 over-expression shows statistical correlation with a panel of key molecular markers such as beta-catenin, e-cadherin, TGFbeta and others, and open the way to further investigations on the EXN32 role in their associated pathways. Overall, results indicate EXN32 as a potential target for the design of novel drugs, such as aptamers, si-RNA and small molecules. The EXN32 specific mAb represents an interesting tool for the molecular characterization of specific cancer subtypes. Investigations are ongoing to understand the predicti