__________________________________________________________________________________________________ Project-3. Combination Therapy: Targeting Pancreatic Cancer with a ROS Inducer and Gemcitabine (PI: Dr. Katie Reindl) Project Summary Pancreatic Cancer (PC) is an extremely deadly disease with a mortality rate of nearly 95%. The current treatment options available for PC patients only extend their lives by a few months. Therefore, there is a critical need to identify potent compounds that could enhance the effectiveness of chemotherapies, especially for K- ras mutant PC cells that are often resistant to treatment. The goal of this research project is to evaluate a novel natural product-based agent in combination with gemcitabine (GEM) for pancreatic cancer therapy, eventually leading to the ultimate development of clinically-useful natural product-based agents for the treatment of cancer. The project objective is to establish piperlongumine (PPLGM) as a chemosensitizer for PC by determining its mechanisms of action and therapeutic efficacy. Our central hypothesis is that PPLGM, isolated from the fruits of long peppers, sensitizes tumor cells, but not normal cells, to chemotherapy-induced cell death through induction of reactive oxygen species (ROS) and enhanced DNA damage. We have formulated this hypothesis based on the existing literature and our own preliminary findings that show PPLGM elevates ROS levels in cancer cells leading to enhanced tumor cell death. To test our central hypothesis, we propose three Specific Aims: 1) To investigate the mechanisms by which PPLGM enhances ROS levels and induces cell death in PC cells; 2) To evaluate the effect of PPLGM on sensitizing PC cells, but not normal cells, to chemotherapy; and 3) To evaluate the therapeutic efficacy of PPLGM alone or in combination with GEM in mouse models of PC. For the first aim, we will treat normal and PC cells that are K-ras mutant and wildtype with PPLGM, and we will determine the molecular mechanisms by which PPLGM causes ROS-induced cell death. For the second aim, we will use the same cells to determine the combined effect of PPLGM and GEM on PC cell death and investigate their synergistic mechanisms for inducing PC cell death. For the third aim, we will evaluate the therapeutic efficacy of PPLGM alone or in combination with GEM using an orthotopic mouse model of K-ras mutant human PC and a transgenic mouse model. The approach uses a novel dietary agent that shows potent anti-cancer effects in the context of chemotherapy for PC. The proposed research is expected to vertically advance and expand understanding of how a ROS-inducing agent can be used as a chemosensitizer for cancer treatment. Ultimately such knowledge has the potential to change the field of chemotherapy and result in more effective treatment for many cancers. __________________________________________________________________________________________________

Public Health Relevance

__________________________________________________________________________________________________ Project-3. Combination Therapy: Targeting Pancreatic Cancer with a ROS Inducer and Gemcitabine (PI: Dr. Katie Reindl) Project Narrative The proposed research aims to provide evidence for the usefulness of a novel ROS-inducing agent with chemosensitizing properties, and to elucidate the mechanisms by which it acts. There is an unmet need for agents that enhance pancreatic cancer treatment, especially for tumors that have K-ras mutations and do not respond well to currently available therapies. This project is relevant to NIH's mission to develop fundamental knowledge that will enhance the effectiveness of current therapies. __________________________________________________________________________________________________

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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North Dakota State University
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Zheng, Wanli; Yao, Li; Teng, Jun et al. (2018) Lateral Flow Test for Visual Detection of Multiple MicroRNAs. Sens Actuators B Chem 264:320-326
Scott, Andrew J; Walker, Sierra A; Krank, Joshua J et al. (2018) AIF promotes a JNK1-mediated cadherin switch independently of respiratory chain stabilization. J Biol Chem 293:14707-14722
Mohammad, Jiyan; Dhillon, Harsharan; Chikara, Shireen et al. (2018) Piperlongumine potentiates the effects of gemcitabine in in vitro and in vivo human pancreatic cancer models. Oncotarget 9:10457-10469
Chikara, Shireen; Mamidi, Sujan; Sreedasyam, Avinash et al. (2018) Flaxseed Consumption Inhibits Chemically Induced Lung Tumorigenesis and Modulates Expression of Phase II Enzymes and Inflammatory Cytokines in A/J Mice. Cancer Prev Res (Phila) 11:27-37
Ray, Priyanka; Confeld, Matthew; Borowicz, Pawel et al. (2018) PEG-b-poly (carbonate)-derived nanocarrier platform with pH-responsive properties for pancreatic cancer combination therapy. Colloids Surf B Biointerfaces 174:126-135
Quadir, Mohiuddin; Fehse, Susanne; Multhaup, Gerhard et al. (2018) Hyperbranched Polyglycerol Derivatives as Prospective Copper Nanotransporter Candidates. Molecules 23:
Xu, Yi; Pang, Lizhi; Wang, Hongzhi et al. (2018) Specific delivery of delta-5-desaturase siRNA via RNA nanoparticles supplemented with dihomo-?-linolenic acid for colon cancer suppression. Redox Biol 21:101085
Karandish, Fataneh; Froberg, James; Borowicz, Pawel et al. (2018) Peptide-targeted, stimuli-responsive polymersomes for delivering a cancer stemness inhibitor to cancer stem cell microtumors. Colloids Surf B Biointerfaces 163:225-235
Guo, Zebin; Zheng, Yafeng; Xu, Hui et al. (2017) Lateral flow test for visual detection of silver (I) based on cytosine-Ag(I)-cytosine interaction in C-rich oligonucleotides. Mikrochim Acta 184:4243-4250
Huang, Yan; Wen, Yongqiang; Baryeh, Kwaku et al. (2017) Lateral flow assay for carbohydrate antigen 19-9 in whole blood by using magnetized carbon nanotubes. Mikrochim Acta 184:4287-4294

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