Abstract 2708: Development of allosteric regulators of the dimerization domains of the plasminogen-related growth factor family for the treatment of pancreatic cancer

Abstract

Abstract The plasminogen-related family of growth factors includes the hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), both of which normally mediate a variety of cellular behaviors including proliferation, survival, and migration. A major contributor to the formation and persistence of various cancers is the dysregulation of these growth factor systems. Overexpression of the HGF receptor, c-Met, is common in many cancers including pancreatic cancer, and is associated with poor prognosis. Dysregulation of this system often leads to tumorigenesis and induction of various malignant phenotypes including increased proliferation, survival, migration, and invasion. In order to activate c-Met, HGF must first undergo an activation step in which it forms an HGF homodimer. Small molecule antagonists with homology to a putative “hinge” region within the HGF sequence have been developed that bind to HGF and allosterically block dimerization, therefore inhibiting c-Met signaling. Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] has previously been shown to inhibit HGF dimerization and HGF-dependent c-Met activation. We have assessed the ability of Norleual to block HGF dimerization and activation of c-Met within pancreatic cancer cells. Similar to the HGF/c-Met system, over-activation of the closely related MSP/Ron (MSP receptor) growth factor system has been identified as a critical contributor to pancreatic cancer progression. Due to overall high sequence homology between HGF and MSP, including the putative “hinge” region, we have hypothesized that MSP must also dimerize in order to efficiently activate the Ron receptor, and that this activation step can be targeted by “hinge” region homologs. Our results indicate that MSP naturally forms dimers and incubation with Norleual and similar “hinge” region antagonists inhibits dimerization. Further, we have demonstrated that MSP dimerization may be biologically significant and inhibition of dimerization suppresses MSP-dependent cell signaling and cell behaviors. The ultimate goal of this work is to develop a dual inhibitor capable of suppressing both the HGF and MSP growth factor systems, and further assess the therapeutic potential of these inhibitors for treatment of pancreatic cancer. Citation Format: Kevin J. Church, Leen Kawas, Joseph Harding, Malte Lang, Michelle McMicheal. Development of allosteric regulators of the dimerization domains of the plasminogen-related growth factor family for the treatment of pancreatic cancer. [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 2708. doi:10.1158/1538-7445.AM2014-2708