Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States. Effective treatment strategies have been elusive as evidenced by typical survival times after diagnosis of <1 year. Pancreatic cancer is characterized clinically by its aggressive metastatic activity and resistance to typical cytotoxic chemotherapeutic agents. Recent studies have implicated the over activation of two growth factor systems macrophage stimulating protein(MSP)/RON (its receptor) and hepatocyte growth factor(HGF)/c- Met(its receptor) as critical contributors to pancreatic cancer's ability to disseminate rapidly and its refractoriness to standard chemotherapy. Thus, the objectives of this project are to develop small molecule MSP antagonists and/or dual acting MSP/HGF antagonists that target the dimerization/activation domain of MSP and MSP/HGF for use as pancreatic cancer therapeutics. To reach these objectives the following specific aims will be addressed. 1) Establish that Macrophage-Stimulating protein (MSP) dimerizes. Demonstrate that a peptide representing the putative dimerization domain of MSP (KDYVRT) can block dimerization. 2) Demonstrate that KDYVRT can inhibit the ability of MSP to activate its receptor, RON, and downstream targets by monitoring its effects on MSP-dependent RON, Gab1, akt, and ERK phosphorylation in HEK293 cells. Further demonstrate that KDYVRT can inhibit MSP-dependent effects on HEK293 migration and proliferation. 3) Evaluate the potential of KDYVRT and related molecules to act as dual MSP/HGF antagonists by assessing the ability of KDYVRT and related molecules to concomitantly inhibit HGF-dependent c-Met activation and HGF-dependent cellular responses in HEK293 cells. 4) Demonstrate that KDYVRT can inhibit the growth and survival of MSP/RON and HGF/c-Met sensitive BxPC3 human pancreatic cancer cells as assessed by fluorescent cell sorting methods. 5) Demonstrate that KDYVRT can suppress the growth and metastasis of BxPC3-luc2 human pancreatic cancer cells in an orthotopic NOD-SCID model using live in vivo imaging methodologies and evaluate the effect of KDYVRT on RON and c-Met activation within the tumors. And, 6) Assuming that KDYVRT is effective at blocking RON activation, a limited number of prototype peptides and peptidomimetic will be synthesized that have improved pharmacokinetic properties. Success of these feasibility studies will spur the synthesis of new dimerization domain based molecules with improved pharmacokinetic properties and better bioavailability. Continued success of the development program should lead to the identification of a lead molecule(s), which would be expected to enter clinical development.
Current therapeutic strategies for treating pancreatic cancer have been abject failures, thus dictating that new and creative treatment approaches be found. This lack of success can be traced to the simultaneous over- activation of two growth factor systems that make the cancer resistant to almost all chemo- and radiation treatments. The goal of this project is to evaluate the therapeutic potential of novel small molecules antagonists of th offending growth factors.
|Church, Kevin J; Vanderwerff, Brett R; Riggers, Rachelle R et al. (2016) Analogs of the hepatocyte growth factor and macrophage-stimulating protein hinge regions act as Met and Ron dual inhibitors in pancreatic cancer cells. Anticancer Drugs 27:766-79|