Exploiting Novel Pathways to Treat Pancreatic Cancer

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DESCRIPTION (provided by applicant): Pancreatic adenocarcinomas are among the most fatal cancers because of their extensive invasion into surrounding tissues and metastasis to distant organs, even at an early stage of tumor progression. The poor prognosis of this malignancy also reflects a generally poor response to current therapies. Thus, a basic understanding of the biology of these tumors and the mechanisms that promote their invasion and metastasis will provide a basis for developing new methods for diagnosis and treatment. Pancreatic adenocarcinomas are characterized by extensive deposition of extracellular matrix, which can have profound effects on cell behavior. We have preliminary studies showing that cells derived from pancreatic adenocarcinomas respond in vitro to exogenous collagen type I by undergoing a transformation from a non-motile epithelial cell to a highly motile and invasive mesenchymal cell. A hallmark of epithelial to mesenchymal transitions is increased expression of N-cadherin, a protein we and others have shown promotes tumor cell invasion. Of particular significance to the current proposal, N-cadherin is expressed by more than 50% of invasive pancreatic tumors. Recent studies have shown that the N-cadherin antagonist, ADH-1 developed by Adherex Technologies, Inc. Durham, NC, inhibits the activity of N-cadherin in vitro and in vivo. We have recently shown that ADH-1 is capable of inhibiting N-cadherin-induced motility in tumor cells, and propose that ADH-1 in combination with the standard of care will reduce pancreatic cancer progression. We will test this hypothesis in a mouse model of invasive pancreatic cancer. In addition, we have characterized the signaling pathways downstream of collagen I that promote up-regulation of N-cadherin and invasion, and propose to test potential inhibitors of various nodes in this pathway for their capability to inhibit pancreatic cancer progression. Public Health Relevance: N-cadherin-expressing pancreatic cancers are more aggressive and more metastatic than N-cadherin null tumors. Here we will identify pathways that promote N-cadherin expression in pancreatic cancers and test the hypothesis that blocking N-cadherin function will limit tumor growth and invasion. Our studies are highly likely to lead to new clinical treatments for human pancreatic cancer.