Abstract 926: The angiotensin IV analog Norleual acts as a hepatocyte growth factor/c-Met inhibitor in pancreatic cancer cells.

Abstract

Abstract The primary purpose of this study was to demonstrate that the hepatocyte growth factor (HGF) antagonist Norleual is capable of attenuating the cellular responses of pancreatic cancer cells to HGF. The angiotensin IV analog Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] exhibits structural homology with the hinge (linker) region of HGF and acts to block HGF dimerization, a process required for its activation. Norleual competitively inhibited the binding of a H3-Hinge peptide sequence to the HGF, and binds directly to HGF with a Ki = 3.6x10-12M. Predictably, Norleual is able to block the cellular responses due to HGF activation in multiple cell types at concentrations in the picomolar range including HGF/c-Met sensitive pancreatic cancer cells. Norleual's ability to inhibit the growth and survival of pancreatic cancer cells was evaluated using viability testing and cell sorting tags to identify living, dead and apoptotic cells. HGF/c-Met activation increases the invasive potential of the pancreatic cancer cells, which provides a mechanistic basis for the ability of c-Met to support pancreatic tumor metastasis. In this regard Norleual as an HGF antagonist was able to block the migration and invasion of pancreatic cancer cells through collagen gels in a transwell chamber. Over-activation of the growth factor system HGF/c-Met is a critical contributor to pancreatic cancer's ability to disseminate rapidly and its refractoriness to standard chemotherapy. Norleual, which is a representative of a “first-in-class” group of molecules that blocks the activation step of HGF, represent a novel therapeutic approach to the treatment of pancreatic cancer. Citation Format: Leen H. Kawas, Phillip Harris, Kevin Church, John W. Wright, Joseph W. Harding. The angiotensin IV analog Norleual acts as a hepatocyte growth factor/c-Met inhibitor in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 926. doi:10.1158/1538-7445.AM2013-926