Pancreatic cancer is resistant to conventional as well as novel anti-cancer therapies including TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). Studies in our laboratories show that triptolide, a compound isolated from the Chinese plant Tripterygium wilfordii, sensitizes pancreatic cancer cells to cell death caused by TRAIL. These novel findings suggest that the combination of TRAIL and triptolide can emerge as an effective therapeutic strategy for pancreatic cancer. Our preliminary studies also provide some mechanistic insights and suggest that triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death by two different mechanisms: 1) by sensitization of the lysosomes to TRAIL induced permeabilization;and 2) by abrogating TRAIL induced NF?B activation, thus counteracting pro-survival pathways induced by TRAIL.
In Aim 1 of the current grant proposal, the efficacy of combination therapy will be evaluated in three unique but complementary animal models of pancreatic cancer.
Aims 2 and 3 are designed to provide insights into the mechanism by which triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death.
In Aim 2 we will evaluate the novel hypothesis that triptolide downregulates Mcl-1, Bcl-2 and Bcl-xl (anti- apoptotic members of Bcl-2 family which sequester Bax/Bak). Release of Bax and Bak, which are then activated by TRAIL, allows them to translocate to lysosomes and induce lysosomal membrane permeabilization).
In Aim 3 we will evaluate the novel hypothesis that triptolide downregulates TRIAL induced NF?B activation by inhibiting cIAP expression. Once unraveled, the mechanisms by which triptolide sensitizes pancreatic cancer cells to TRAIL will lead to the development of novel drug targets. Successful completion of these mechanistic and translational studies will eventually help in planning strategies to combine triptolide with TRAIL so that this combination can be used for the treatment of pancreatic cancer.

Public Health Relevance

Pancreatic cancer is resistant to conventional as well as novel anti-cancer therapies including TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). Studies in our laboratories show that triptolide, a compound isolated from the Chinese plant Tripterygium wilfordii, sensitizes pancreatic cancer cells to cell death caused by TRAIL. In the current grant proposal, we intend to confirm the efficacy of the combination of TRAIL and triptolide against pancreatic cancer in animal models of pancreatic cancer, and investigate the mechanism of action of this combined therapy. Once unraveled, the mechanisms by which triptolide sensitizes pancreatic cancer cells to TRAIL will lead to the development of novel drug targets. Successful completion of these mechanistic and translational studies will eventually help in planning strategies to combine triptolide with TRAIL so that this combination can be used for the treatment of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA170946-02
Application #
8507185
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Fu, Yali
Project Start
2012-07-06
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$452,316
Indirect Cost
$154,740
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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
Modi, Shrey; Kir, Devika; Giri, Bhuwan et al. (2016) Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer. J Gastrointest Surg 20:13-23; discussion 23-4
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
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
Sangwan, Veena; Banerjee, Sulagna; Jensen, Kelsey M et al. (2015) Primary and liver metastasis-derived cell lines from KrasG12D; Trp53R172H; Pdx-1 Cre animals undergo apoptosis in response to triptolide. Pancreas 44:583-9
Brincks, Erik L; Kucaba, Tamara A; James, Britnie R et al. (2015) Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma. FEBS J 282:4747-65
Nomura, Alice; McGinn, Olivia; Dudeja, Vikas et al. (2015) Minnelide effectively eliminates CD133(+) side population in pancreatic cancer. Mol Cancer 14:200
Nomura, Alice; Banerjee, Sulagna; Chugh, Rohit et al. (2015) CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer. Oncotarget 6:8313-22
Banerjee, Sulagna; Nomura, Alice; Sangwan, Veena et al. (2014) CD133+ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide. Clin Cancer Res 20:2388-99

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