Pancreatic adenocarcinoma (PCA) remains a fatal disease with extremely poor prognosis, despite advances in the understanding of molecular mechanisms in cancer biology. This may be attributed to the failure in translating the acquired knowledge into viable therapeutics. Towards this end, we have defined a novel regulatory role for the protein GIPC in pancreatic cancer growth and metastasis, and identified it as a plausible target for pancreatic cancer therapy. GIPC binds to various endogenous proteins with its PDZ domain. Our published results suggest that either depletion of GIPC expression, or disruption of PDZ domain- binding between GIPC and endogenous partner proteins (such as IGF-1R or endoglin) via peptide-based inhibitors, elicits a significant inhibitory response in pancreatic cancer growth. We have also shown that pancreatic cancer cells with depleted GIPC expression exhibited an increase in autophagy and exosome biogenesis, and enhanced sensitivity towards the conventional drug gemcitabine. Furthermore, our preliminary data indicate that GIPC binding partners and downstream signaling molecules are differentially regulated in different subgroups of PCA. Taken together, these observations have led us to hypothesize that inactivation of GIPC function, by disrupting the binding of GIPC with subgroup-specific endogenous partner proteins, can be exploited to inhibit signaling pathways important for cancer progression, metastasis and drug resistance in various subgroups of PCA. This would have important clinical implications towards the development of personalized therapy for treating pancreatic cancer. To test our hypothesis, we have proposed two aims.
Aim 1 will focus on developing a new generation of highly selective and potent peptide and small molecule inhibitors of GIPC, with the help of NMR spectrometry and X-ray crystallography, the latter which has recently yield the first structure of GIPC bound to one of our inhibitors.
Aim 2 will focus on determining how GIPC and its partner proteins differentially regulate various downstream signaling pathways in different subgroups of PCA, and designing new individualized therapy for pancreatic cancer based on the this acquired knowledge. Overall, these studies will help us to develop novel personalized therapeutic strategies for different subgroups of PCA, by combining conventional drugs with newly-developed pathway- specific inhibitors of GIPC, which can be translated to fast track clinical trials in the near future.

Public Health Relevance

Pancreatic adenocarcinoma (PCA) is an aggressive disease with poor prognosis. This work will focus on developing new personalized therapeutics for various subgroups of pancreatic cancer. Our proposed experiments will illuminate the regulatory role of GIPC, its binding partners within the cell, and their downstream molecules in tumor growth, metastasis and drug resistance in different subgroups of PCA. We will use the accumulate knowledge from these studies to develop novel peptide and small molecule inhibitors of GIPC, which may serve as individualized, molecular therapeutics for the treatment of different subgroups of PCA.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA150190-06A1
Application #
9247285
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2010-04-07
Project End
2022-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
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
Javeed, Naureen; Mukhopadhyay, Debabrata (2017) Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res 31:386-394
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
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
Tan, Xiang-Lin; Bhattacharyya, Kalyan K; Dutta, Shamit K et al. (2015) Metformin suppresses pancreatic tumor growth with inhibition of NF?B/STAT3 inflammatory signaling. Pancreas 44:636-47
Patra, Chitta Ranjan; Rupasinghe, Chamila N; Dutta, Shamit K et al. (2015) Chemically-Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer. ACS Chem Biol :
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
Hoeppner, Luke H; Wang, Ying; Sharma, Anil et al. (2015) Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells. Mol Oncol 9:270-81

Showing the most recent 10 out of 35 publications