Targeting Nrf2 for Cancer Chemoprevention

 描述（由申请人提供）：环境致癌物和其他有毒物质导致世界各地许多人群的癌症和其他慢性疾病负担不断增加。有必要查明这些促成因素，确定其不断变化的接触模式，并制定预防战略，以减轻其对健康的影响。减少接触食物和空气传播的有毒物质需要大量的经济和政治投资，这些投资由国家和全球任务驱动，但事实证明这些任务很难执行。我推测，化学预防，特别是食物为基础的化学预防，提供了一个实际的机会，以减少与这些“不可避免的”或很大程度上难以处理的暴露相关的风险。我的临床前和临床工作，专注于与翻译相结合的机制，通过激活Keap 1-Nrf 2细胞保护信号通路，以安全，廉价和有效的干预措施来增强环境致癌物的解毒作用。在过去的十年中，我花了很多时间来验证Keap 1-Nrf 2信号通路的激活是否是癌症预防的一个合适的靶点。在癌症预防中有用的药剂需要对特定的生物学途径具有强作用和最小的脱靶效应，特别是那些驱动剂量限制性毒性的脱靶效应。确认化合物影响预期靶点和鉴定不期望的副作用是开发新药的主要挑战。目前在开发和实施这种化学预防方法方面的差距包括需要更敏感的生物标志物来测量其药效学作用，以及更清楚地了解Nrf 2途径持续（或间歇）激活对保护和可能的不良作用的全面影响。因此，在OIA申请中，我建议追求两个互补的主题：（i）开发和验证Nrf 2适应性应激反应途径激活剂的药效学作用的生物标志物，以及（ii）评估可能的Nrf 2“应激反应成瘾”的体内后果。这项工作将由一个创新的、富有成效的和高度被引用的实验室团队进行，并将导致Nrf 2信号传导的优化靶向，以预防癌症和其他慢性疾病。

 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.