Targeting Nrf2 for Cancer Chemoprevention

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 DESCRIPTION (provided by applicant): 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.