Inhibitors of N-cadherin in the treatment of pancreatic cancer
Project Leaders: Keith R. Johnson, Ph.D. and Jean Grem, M.D.
Translational Goal: Evaluate the efficacy and mechanism of action of a novel therapeutic (Exherin) that inhibits activity of N-cadherin, in the treatment of pancreatic cancer.
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. In addition, our data and that from the literature show that ADH-1 induces apoptosis in an N-cadherin-dependent manner. We hypothesize that ADH-1 is capable of inhibiting tumor growth and metastasis in N-cadherin-expressing pancreatic cancer cells, and propose to test this hypothesis in N-cadherin-expressing pancreatic cancer cells in a mouse model of invasive pancreatic cancer. In addition, we propose to characterize the signaling pathways downstream of collagen I that promote up-regulation of N-cadherin and invasion, for the purpose of identifying potential inhibitors that could be used in combination therapy with ADH-1. Finally, we will test the efficacy of ADH-1 as a treatment for human pancreatic cancer in clinical trials.
Keith R. Johnson, Ph.D.
UNMC College of Dentistry
Jean Grem, M.D.
UNMC Internal Medicine