Norleual A Hepatocyte Growth Factor/C-Met Inhibitor Blocks Malignant Phenotypes In Cancerous Cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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 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, norleulal 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 several cell lines including 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 cancer cells through collagen gels in a transwell chamber. Over-activation of the growth factor system HGF/c-Met is a critical contributor to 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 HGF/Met sensitive cancers including pancreatic cancer. Citation Format: Leen H. Kawas, Kevin J. Church, Malte Lange, Michelle Mcmicheal, Brent Yamamoto, Joseph W. Harding. Norleual a hepatocyte growth factor/c-Met inhibitor blocks malignant phenotypes in cancerous cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 729. doi:10.1158/1538-7445.AM2014-729