Environmental carcinogens and other toxicants contribute to the increasing burden of cancer and other chronic diseases in many populations across the world. There are needs to identify these contributing agents, determine their changing exposure patterns and design prevention strategies to mitigate their health impact. Reductions in exposures to food- and air-borne toxicants require substantive economic and political investments, driven by national and global mandates, which have proven difficult to implement. I hypothesize that chemoprevention, especially food-based chemoprevention, offers a practical opportunity to reduce risks associated with these unavoidable or largely intractable exposures. My preclinical and clinical efforts, focused on mechanisms coupled with translation, have targeted enhanced detoxication of environmental carcinogens through activation of the Keap1-Nrf2 cytoprotective signaling pathway with safe, inexpensive and effective interventions. I have spent much of the past decade validating activation of the Keap1-Nrf2 signaling pathway as an opportune target in cancer prevention. Useful agents in cancer prevention need to have strong effects on specific biological pathway(s) and minimal off-target effects, especially those driving dose-limiting toxicities. Confirmation that a compound affects the intended target(s) and identification of undesirable secondary effects are among the main challenges in developing new drugs. Current gaps in the development and implementation of this chemopreventive approach include a need for more sensitive biomarkers to measure their pharmacodynamic action, and a clearer understanding of the full breadth of effects of sustained (or intermittent) activation of the Nrf2 pathway on both protective and possible adverse actions. Therefore, in the OIA application, I propose to pursue two complementary themes: (i) development and validation of biomarkers of pharmacodynamic action of activators of the Nrf2 adaptive stress response pathway, and (ii) evaluation of the consequences in vivo of possible Nrf2 stress response addiction. This work will be conducted by an innovative, productive and highly cited laboratory team and will lead to optimized targeting of Nrf2 signaling for prevention of cancer and other chronic diseases.

Public Health Relevance

Critical environmental exposures contribute to cancer and other chronic diseases across the life span, especially in economically developing regions of the world. While reductions in exposures will require substantive economic and political investments, chemoprevention trials, especially the food-based 'green' chemoprevention, offer opportunities for individuals to mitigate risks associated with these unavoidable exposures. This research will optimize the use of the transcription factor Nrf2 as a target for cancer chemoprevention by developing biomarkers of pharmacodynamics action and assessing the consequences of 'stress response addiction' through over-stimulation of the pathway. Collectively, these studies will facilitate the identification and utilization of safe, efficacious chemopreventive agents in clinical interventions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Unknown (R35)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Miller, Mark S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Palliyaguru, Dushani L; Yuan, Jian-Min; Kensler, Thomas W et al. (2018) Isothiocyanates: Translating the Power of Plants to People. Mol Nutr Food Res 62:e1700965
Chartoumpekis, Dionysios V; Yagishita, Yoko; Fazzari, Marco et al. (2018) Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice. JCI Insight 3:
Wible, Ryan S; Tran, Quynh T; Fathima, Samreen et al. (2018) Pharmacogenomics of Chemically Distinct Classes of Keap1-Nrf2 Activators Identify Common and Unique Gene, Protein, and Pathway Responses In Vivo. Mol Pharmacol 93:297-308
Chartoumpekis, Dionysios V; Palliyaguru, Dushani L; Wakabayashi, Nobunao et al. (2018) Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term high-fat diet-induced obesity in mice. Am J Physiol Endocrinol Metab 315:E180-E195
Chen, Taoyang; Qian, Gengsun; Fan, Chunsun et al. (2018) Qidong hepatitis B virus infection cohort: a 25-year prospective study in high risk area of primary liver cancer. Hepatoma Res 4:
Wible, Ryan S; Ramanathan, Chidambaram; Sutter, Carrie Hayes et al. (2018) NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus. Elife 7:
Ramadori, Pierluigi; Drescher, Hannah; Erschfeld, Stephanie et al. (2017) Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte-Specific c-met Deletion during the Progression of NASH. Oxid Med Cell Longev 2017:3420286
Lu, Kevin; Alcivar, Allen L; Ma, Jianglin et al. (2017) NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress-Induced DPP3-KEAP1 Interaction. Cancer Res 77:2881-2892
Dinkova-Kostova, Albena T; Fahey, Jed W; Kostov, Rumen V et al. (2017) KEAP1 and Done? Targeting the NRF2 Pathway with Sulforaphane. Trends Food Sci Technol 69:257-269
Livingstone, Merricka C; Johnson, Natalie M; Roebuck, Bill D et al. (2017) Profound changes in miRNA expression during cancer initiation by aflatoxin B1 and their abrogation by the chemopreventive triterpenoid CDDO-Im. Mol Carcinog 56:2382-2390

Showing the most recent 10 out of 20 publications