Targeting Nrf2 for Cancer Chemoprevention

靶向 Nrf2 进行癌症化学预防

• 批准号: 10194395
• 负责人: THOMAS W KENSLER
• 金额: $ 72.57万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194395
• 关键词: Affect; Air; Automobile Driving; Biological; Biological Markers; Cancer Burden; Chemoprevention; Chemopreventive Agent; Chronic Disease; Clinical; Coupled; Development; Dose-Limiting; Economics; Environmental Carcinogens; Environmental Exposure; Evaluation; Exposure to; Food; Health; Individual; Intervention; Investments; Laboratories; Longevity; Malignant Neoplasms; Measures; Pathway interactions; Pattern; Pharmacodynamics; Politics; Population; Prevention strategy; Research; Risk; Signal Pathway; Signal Transduction; Toxic effect; Translations; Work; addiction; base; biological adaptation to stress; biomarker validation; cancer chemoprevention; cancer prevention; design; detoxication; effective intervention; in vivo; innovation; novel therapeutics; pharmacodynamic biomarker; pre-clinical; public health relevance; toxicant; transcription factor

 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.

 描述(申请人提供)：环境致癌物质和其他有毒物质在世界各地的许多人口中增加了癌症和其他慢性病的负担。需要确定这些致病因素，确定其不断变化的暴露模式，并制定预防战略，以减轻其对健康的影响。减少对食物和空气传播的毒物的暴露需要在国家和全球任务的推动下进行大量的经济和政治投资，而事实证明，这些任务很难执行。我假设，化学预防，特别是以食物为基础的化学预防，提供了一个实际机会来降低与这些“不可避免的”或基本上难以解决的暴露相关的风险。我的临床前和临床工作，重点是结合翻译的机制，通过安全、廉价和有效的干预措施激活Keap1-Nrf2细胞保护信号通路来增强环境致癌物的解毒作用。在过去十年的大部分时间里，我一直在验证Keap1-Nrf2信号通路的激活是预防癌症的一个合适的靶点。在癌症预防中有用的药物需要对特定的生物途径有很强的作用(S)和最小的非靶点效应，特别是那些驱动剂量限制毒性的药物。确认一种化合物影响预期的目标(S)和识别不良的副作用是开发新药的主要挑战之一。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记物来衡量其药效作用，以及更清楚地了解持续(或间歇性)激活Nrf2途径对保护性和可能的不良反应的全面影响。因此，在OIA的申请中，我建议追求两个互补的主题：(I)开发和验证Nrf2适应性应激反应途径激活剂的药效作用生物标记物，以及(Ii)评估可能的Nrf2“应激反应成瘾”在体内的后果。这项工作将由一个创新的、富有成效的和经常被引用的实验室团队进行，并将导致优化Nrf2信号的目标，以预防癌症和其他慢性疾病。