Emerging research in cancer therapy is focused on exploiting the biochemical differences between cancer cell and normal cell metabolism. The Warburg effect is a fundamental change in many malignant cancer cells and is the shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. The common perception is that this metabolic reprogramming provides the cellular energy required for unregulated cell growth, invasion, and metastasis. Human pancreatic ductal adenocarcinoma (PDAC) is an incurable and highly aggressive human cancer. The median survival of the 75-80% of patients with malignant PDAC at the time of initial diagnosis is 6-months. Standard chemotherapy with the cytolytic drug gemcitabine provides a slight survival benefit. Thus, there is an unmistakable and critical unmet need for new therapies to treat patients with pancreatic cancer. The overall goal of this project is to develop new therapeutic approaches to inhibit PDAC malignancy. The significance of the proposed work lies in the use of relatively nontoxic mitochondria-targeted cationic drugs in combination with glycolytic and glutaminolytic energy metabolism inhibitors to decrease pancreatic cancer cell proliferation and metastasis. The overarching hypothesis is that a combination of glycolytic, glutaminolytic, and/or mitochondrial metabolism inhibitors with standard therapies will deplete ATP, decrease energy sensing, proliferation, and migration in vitro, and inhibit aerobic glycolysis and human PDAC tumor growth and metastasis in vivo. Studies in Aim 1 will use innovative high-throughput and mass spectroscopy-based metabolomics approach to investigate bioenergetic changes in glycolysis, tricarboxylic acid cycle, and glutaminolysis in human primary PDAC cells treated with mitochondria-targeted cationic agents, and/or inhibitors of energy metabolism.
Aim 2 will use cell culture approaches to define the role for bioenergetic metabolism inhibitors in activating energy regulatory signaling pathways and altering PDAC growth, invasion, and migration.
Aim 3 will use preclinical hyperpolarized magnetic resonance and bioluminescence imaging techniques to screen the in vivo efficacy of targeted drugs that inhibit energy metabolism, alone or in combination with traditional chemotherapy to mitigate PDAC growth and metastasis. The overall impact of the proposed work is two-fold: First, it will advance our understanding of the role of metabolism, energetics, and energy sensing in pancreatic cancer malignancy and second it will engender the design and testing of drugs that stifle energy production and which may ultimately be translated to the clinic.

Public Health Relevance

The research proposed in this application is relevant to public health because pancreatic ductal adenocarcinoma is a uniformly catastrophic malignancy with a 5-year survival rate less than 6%. There is a marked paucity of drugs to treat patients with pancreatic cancer and none that act on the mitochondrial bioenergetic pathway of malignant cells. The strategy of the proposed investigations is to inhibit bioenergetic metabolism with relatively non-toxic mitochondria-targeted drugs, in combination with glycolysis inhibitors and conventional therapies, to diminish the severity of this disease and improve the health of patients with pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA178960-01A1
Application #
8696182
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2014-07-01
Project End
2019-05-31
Budget Start
2014-07-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Zielonka, Jacek; Kalyanaraman, Balaraman (2018) Small-molecule luminescent probes for the detection of cellular oxidizing and nitrating species. Free Radic Biol Med 128:3-22
Cheng, Gang; Zielonka, Monika; Dranka, Brian et al. (2018) Detection of mitochondria-generated reactive oxygen species in cells using multiple probes and methods: Potentials, pitfalls, and the future. J Biol Chem 293:10363-10380
Kalyanaraman, Balaraman; Cheng, Gang; Hardy, Micael et al. (2018) A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds. Redox Biol 14:316-327
Boyle, Kathleen A; Dwinell, Michael B (2018) GEMMs Are a Gem When it Comes to Defining the Role of HIF2? in Mucinous Cystic Neoplasms. Cell Mol Gastroenterol Hepatol 5:165-166
Kalyanaraman, Balaraman; Cheng, Gang; Zielonka, Jacek et al. (2018) Low-Temperature EPR Spectroscopy as a Probe-Free Technique for Monitoring Oxidants Formed in Tumor Cells and Tissues: Implications in Drug Resistance and OXPHOS-Targeted Therapies. Cell Biochem Biophys :
Boyle, Kathleen A; Van Wickle, Jonathan; Hill, R Blake et al. (2018) Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation. J Biol Chem 293:14891-14904
Kalyanaraman, Balaraman; Cheng, Gang; Hardy, Micael et al. (2018) Teaching the basics of reactive oxygen species and their relevance to cancer biology: Mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies. Redox Biol 15:347-362
Kalyanaraman, Balaraman (2017) Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism. Redox Biol 12:833-842
Kalyanaraman, Balaraman; Zielonka, Jacek (2017) Green fluorescent proteins induce oxidative stress in cells: A worrisome new wrinkle in the application of the GFP reporter system to biological systems? Redox Biol 12:755-757
Kalyanaraman, Balaraman; Cheng, Gang; Hardy, Micael et al. (2017) Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies. Cell Biochem Biophys 75:311-317

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