Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Furthermore, conventional treatment generally fails because of a significant gap in translating the molecular mechanisms of carcinogenesis into feasible therapeutics. Overexpression of many mitogenic growth factors and their receptors, in particular the overexpression of IGF-1R and EGFR, has been observed with a high frequency in patients with advanced pancreatic cancer. Several studies have been completed in an attempt to understand the pathways that lead to IGF-1R and EGFR-mediated signaling, but the molecular mechanism of receptor overexpression remains unclear. In our published as well as preliminary studies, we have defined a unique mechanism of IGF-1R and EGFR overexpression in PCA. Our data also define a novel regulatory role of GIPC, a RGS/PDZ binding protein, which controls both IGF-1R and EGFR expression by two distinct mechanisms. Moreover, we have also shown that pancreatic cancer cells expressed shRNA of GIPC grow significantly slower than that of parental cells, and their metastasis capabilities are restricted. Our recent published results have also encouraged us to propose a targeted therapeutic approach using nanotechnology to improve drug delivery methods. Taken together, these observations have led us to hypothesize that inactivation of GIPC function can be exploited to inhibit IGF-1R and EGFR overexpression in a targeted manner that would have important clinical implications in PCA. To test our hypothesis, we have proposed four aims.
Aim 1 will examine the molecular mechanism of the regulatory role of GIPC on IGF-1R and EGFR overexpression in PCA cells.
Aim 2 will develop chemical discovery platforms for identifying novel peptide-based ligands for GIPC.
In Aim 3, we will focus on biochemical characterization and cellular probe development of peptide-based ligands for GIPC.
Aim 4 will focus on the development of nanotechnology-based targeted therapeutics. We will synthesize and characterize in vitro the different combinations of anti-IGF-1R antibody, GIPC peptides (IGF-1R and EGFR inhibitors) attached onto the surface of gold nanoparticles with or without gemcitabine. In the later part of this aim, we will extrapolate the knowledge and reagents from the previous aims to the animal model of orthotropic pancreatic cancer that can mimic human diseases. We will examine the in vivo efficacy of the nanogold conjugated drugs in vivo seeking to understand the importance of multi-targeted, combination drugs in PCA progression and metastasis. Furthermore, we will determine pharmacokinetics, pharmacodynamics, bio-distribution, and bio-toxicity of the effective drugs that will lead us toward clinical trials in the near future. Overall, our highly collaborative proposed experiments will identify specific targets for therapeutic interventions for pancreatic adenocarcinoma where no current therapy is available.

Public Health Relevance

Pancreatic adenocarcinoma (PaCA) is, almost invariably, a fatal disease. This work will focus on the prevention and therapeutic aspects of this cancer. Overall, our proposed experiments will define the regulatory role of GIPC and their downstream molecules that can influence the tumor growth and metastasis. The proposed study might define the mechanism of pancreatic cancer growth and progression and identify specific targets for therapeutic interventions for pancreatic adenocarcinoma where no current therapy is available.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA150190-05
Application #
8607838
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
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