Dissertation
Investigation of the Therapeutic Potential of Novel Hepatocyte Growth Factor and Macrophage Stimulating Protein Antagonists for the Treatment of Pancreatic Cancer
Doctor of Philosophy (PhD), Washington State University
01/2016
Handle:
https://hdl.handle.net/2376/117290
Abstract
Pancreatic cancer is a deadly disease that is characterized by low survival rates, aggressive progression, and chemoresistance largely due to the activity of the hepatocyte growth factor (HGF)/Met (HGF receptor) and macrophage stimulating protein (MSP)/Ron (MSP receptor) growth factor systems. These systems are frequently over-activated in pancreatic cancer and contribute strong mitogenic, motogenic, and pro-survival signals to the cancer cells. Due to their importance in pancreatic cancer, they have been considered as appealing therapeutic targets and considerable efforts are underway to develop effective therapies that specifically target and inhibit the HGF/Met and MSP/Ron systems.
Our laboratory has developed novel inhibitors in the form of small peptides that mimic the hinge region within the HGF sequence. The hinge region is essential for HGF/Met signaling, and previous reports from our laboratory have shown that these compounds, termed hinge analogs, can bind to HGF and inhibit HGF-induced Met activation and related cell behaviors. Given the extensive similarities between HGF and MSP, we likewise produced a peptide mimetic of the corresponding hinge region in MSP to determine if a similar strategy used to inhibit HGF could also antagonize MSP. Here, I demonstrate the hinge analogs, including HGF Hinge, MSP Hinge, Norleual, and D-Norisoleual, can inhibit HGF activity in pancreatic cancer cells. I also present evidence that the hinge analogs block MSP activity and thus act as dual HGF/MSP inhibitors.
In this dissertation I will describe the results of in vitro experiments investigating the effects of hinge analogs, particularly Norleual, on HGF/Met and MSP/Ron signaling and malignant cell behaviors including proliferation, migration, and invasion in pancreatic cancer cells. Here, I also present the results of an in vitro analysis of select hinge analogs on the survival and cell signaling of pancreatic cancer cells when given concurrently with a cytotoxic chemotherapeutic agent. I will also detail the results of an in vivo assessment of the effects of Norleual treatment, in conjunction with the chemotherapeutic gemcitabine, on tumor growth in a mouse model of pancreatic cancer. Furthermore, I will describe the results of preliminary studies investigating the anti-cancer activity of a next-generation hinge analog; D-Norisoleual.
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Details
- Title
- Investigation of the Therapeutic Potential of Novel Hepatocyte Growth Factor and Macrophage Stimulating Protein Antagonists for the Treatment of Pancreatic Cancer
- Creators
- Kevin Church
- Contributors
- Joseph Harding (Advisor)John Wright (Committee Member)Mary Hunzicker-Dunn (Committee Member)Michael Konkel (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Molecular Biosciences, School of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 169
- Identifiers
- 99900581523501842
- Language
- English
- Resource Type
- Dissertation