Pancreatic cancer is a devastating disease with a poor prognosis. The severity of this malignancy can be appreciated from the fact that in 2012 over 44,000 new cases of pancreatic cancer are expected, with almost the same number succumbing to this disease. Studies in our laboratory have shown that triptolide, a natural compound, induces cell death in pancreatic cancer cells and is very effective in reducing tumor growth and loco-regional spread in an orthotopic model of pancreatic cancer. To expedite the clinical application of this compound we have synthesized a water soluble analog of triptolide named Minnelide. Minnelide also is very effective against pancreatic cancer in multiple animal models and will soon be evaluated against pancreatic cancer in phase I clinical trials. The overall goal of the current grant proposal is to elucidate the mechanism by which triptolide induces cell death in pancreatic cancer cells. We believe that defining this mechanism will lead to novel insights into the pathogenesis of cancer and reveal novel approaches to tackle the resistance of pancreatic cancer cells to cell death. We have previously demonstrated that one of the mechanisms by which triptolide induces cell death is by downregulating the pro-survival protein HSP70. However, we believe that triptolide modulates multiple pro-survival pathways and elucidating these pathways would lead to development of novel drug targets. Intriguingly, our preliminary data suggest that triptolide induces ER stress and inhibits NFkB by downregulating Specificity protein1 (Sp1). Our preliminary data also provide novel insight into the mechanism by which triptolide induced ER stress causes cell death by inducing lysosomal membrane permeabilization (LMP) and NFkB inhibition results in inhibition of HSP70, leading to cell death. In the current grant proposal, we will build on these preliminary findings.
Aim 1 of th current grant proposal is geared towards evaluating the mechanism by which triptolide downregulates Sp1.
Aim 2 and 3 are focused on the evaluation of the role of triptolide induced Sp1 downregulation in induction of ER stress and NFkB inhibition. The experiments proposed in the current proposal will elucidate novel mechanisms by which Sp1 can modulate ER stress and NFkB and by which ER stress and NFkB inhibition can lead to cell death by inducing lysosomal membrane permeabilization and HSP70 downregulation respectively. These mechanisms have not been studied in any cell system till date. We believe that successful completion of these studies will not only elucidate the mechanism of action of triptolide but also will lead to the discovery of novel drug targets eventually leading to development of novel therapies against pancreatic cancer.

Public Health Relevance

Pancreatic cancer is associated with poor prognosis and resistance to current therapeutic regimens. We have synthesized Minnelide, a water soluble variant of triptolide, which will be entering Phase I clinical trials shortly. Preclinical studies ith this drug have shown great promise. However, the mechanism of action of triptolide is poorly understood. In the current grant proposal, we aim to investigate the mechanism of action of this therapy. Once unraveled, the mechanisms by which triptolide kills pancreatic cancer cells will lead to the development of novel drug targets. Successful completion of these mechanistic and translational studies will eventually help in planning strategies for the treatment of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124723-10
Application #
9302300
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Salnikow, Konstantin
Project Start
2007-09-24
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Garg, Bharti; Giri, Bhuwan; Modi, Shrey et al. (2018) NF?B in Pancreatic Stellate Cells Reduces Infiltration of Tumors by Cytotoxic T Cells and Killing of Cancer Cells, via Up-regulation of CXCL12. Gastroenterology 155:880-891.e8
Dauer, Patricia; Zhao, Xianda; Gupta, Vineet K et al. (2018) Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression. Cancer Res 78:1321-1333
Nomura, Alice; Gupta, Vineet K; Dauer, Patricia et al. (2018) NF?B-Mediated Invasiveness in CD133+ Pancreatic TICs Is Regulated by Autocrine and Paracrine Activation of IL1 Signaling. Mol Cancer Res 16:162-172
Sethi, Vrishketan; Kurtom, Saba; Tarique, Mohammad et al. (2018) Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response. Gastroenterology 155:33-37.e6
Giri, Bhuwan; Sethi, Vrishketan; Modi, Shrey et al. (2017) ""Heat shock protein 70 in pancreatic diseases: Friend or foe"". J Surg Oncol 116:114-122
Sethi, Vrishketan; Giri, Bhuwan; Saluja, Ashok et al. (2017) Insights into the Pathogenesis of Pancreatic Cystic Neoplasms. Dig Dis Sci 62:1778-1786
Dauer, Patricia; Gupta, Vineet K; McGinn, Olivia et al. (2017) Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer. Sci Rep 7:1564
McGinn, Olivia; Gupta, Vineet K; Dauer, Patricia et al. (2017) Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer. Sci Rep 7:7872
Isharwal, Sumit; Modi, Shrey; Arora, Nivedita et al. (2017) Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants. Prostate 77:584-596
Dauer, Patricia; Nomura, Alice; Saluja, Ashok et al. (2017) Microenvironment in determining chemo-resistance in pancreatic cancer: Neighborhood matters. Pancreatology 17:7-12

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