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 #
5R01CA124723-07
Application #
8683117
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Salnikow, Konstantin
Project Start
2007-09-24
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Dauer, Patricia; Zhao, Xianda; Gupta, Vineet K et al. (2017) Inactivation of cancer-associated-fibroblasts (CAF) disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression. Cancer Res :
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Sethi, Vrishketan; Giri, Bhuwan; Saluja, Ashok et al. (2017) Insights into the Pathogenesis of Pancreatic Cystic Neoplasms. Dig Dis Sci 62:1778-1786
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
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
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
Majumder, Kaustav; Arora, Nivedita; Modi, Shrey et al. (2016) A Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies. J Gastrointest Surg 20:53-65; discussion 65
Banerjee, Sulagna; Modi, Shrey; McGinn, Olivia et al. (2016) Impaired Synthesis of Stromal Components in Response to Minnelide Improves Vascular Function, Drug Delivery, and Survival in Pancreatic Cancer. Clin Cancer Res 22:415-25
Modi, Shrey; Kir, Devika; Banerjee, Sulagna et al. (2016) Control of Apoptosis in Treatment and Biology of Pancreatic Cancer. J Cell Biochem 117:279-88
Nomura, Alice; Majumder, Kaustav; Giri, Bhuwan et al. (2016) Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer. Lab Invest 96:1268-1278

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