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.
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.
|Vivekanandhan, Sneha; Mukhopadhyay, Debabrata (2018) Genetic status of KRAS influences Transforming Growth Factor-beta (TGF-?) signaling: An insight into Neuropilin-1 (NRP1) mediated tumorigenesis. Semin Cancer Biol :|
|Wang, Ying; Wang, Enfeng; Zhang, Yuebo et al. (2018) Neuropilin-1 maintains dimethylarginine dimethylaminohydrolase 1 expression in endothelial cells, and contributes to protection from angiotensin II-induced hypertension. FASEB J :fj201800499R|
|Vivekanandhan, Sneha; Yang, Lijuan; Cao, Ying et al. (2017) Genetic status of KRAS modulates the role of Neuropilin-1 in tumorigenesis. Sci Rep 7:12877|
|Javeed, Naureen; Mukhopadhyay, Debabrata (2017) Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res 31:386-394|
|Pal, Krishnendu; Al-Suraih, Farah; Gonzalez-Rodriguez, Roberto et al. (2017) Multifaceted peptide assisted one-pot synthesis of gold nanoparticles for plectin-1 targeted gemcitabine delivery in pancreatic cancer. Nanoscale 9:15622-15634|
|Sagar, Gunisha; Sah, Raghuwansh P; Javeed, Naureen et al. (2016) Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. Gut 65:1165-74|
|Alam, S K; Yadav, V K; Bajaj, S et al. (2016) DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. Cell Death Differ 23:707-22|
|Mondal, Sujan Kumar; Jinka, Sudhakar; Pal, Krishnendu et al. (2016) Glucocorticoid Receptor-Targeted Liposomal Codelivery of Lipophilic Drug and Anti-Hsp90 Gene: Strategy to Induce Drug-Sensitivity, EMT-Reversal, and Reduced Malignancy in Aggressive Tumors. Mol Pharm 13:2507-23|
|Wang, Ying; Cao, Ying; Yamada, Satsuki et al. (2015) Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-? Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1? and Mitochondrial Homeostasis. Arterioscler Thromb Vasc Biol 35:1401-12|
|Hoeppner, Luke H; Sinha, Sutapa; Wang, Ying et al. (2015) RhoC maintains vascular homeostasis by regulating VEGF-induced signaling in endothelial cells. J Cell Sci 128:3556-68|
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