Targeting Heme Metabolism for the Treatment of KRAS- KEAP1-Mutant Lung Adenocarcinoma

靶向血红素代谢治疗 KRAS-KEAP1 突变型肺腺癌

• 批准号: 9909631
• 负责人: Warren Wu
• 金额: $ 5.05万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909631
• 关键词: Address; Adult; Anemia; Antioxidants; Bilirubin; Biochemical; Carbon Monoxide; Catabolism; Cells; Cessation of life; Chronic; Clinical; Complex; Data; Dependence; Development; Disease; Disease Progression; Electron Transport; Enzymes; Event; Fellowship; General Population; Genes; Genetic; Genetic Determinism; Genetically Engineered Mouse; Genotype; Heme; Hemoglobin; Hepatic Porphyrias; Homeostasis; Immune Evasion; Inherited; KRAS2 gene; Lead; Link; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Outcome; Oxidation-Reduction; Oxygen; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Play; Pre-Clinical Model; Production; Prosthesis; Reaction; Regulatory Pathway; Reporting; Research; Role; Severity of illness; Signal Pathway; Signal Transduction; Solid; Symptoms; Techniques; Testing; Therapeutic; Transplantation; Work; base; cancer cell; cancer genetics; cancer therapy; design; driver mutation; efficacy testing; heme biosynthesis; heme oxygenase-1; immune checkpoint blockade; immunoregulation; improved; in vivo; interest; loss of function; lung development; mutant; neoplastic cell; new therapeutic target; novel; outcome forecast; precision medicine; response; targeted treatment; therapeutic target; transcription factor; tumor; tumorigenesis

Project Abstract KRAS-driven lung adenocarcinoma (LUAD) represents a major non-small cell lung cancer (NSCLC) genetic subtype for which treatment options remain limited. Mutations in the KEAP1/NRF2 signaling pathway are common events in several solid cancers, including KRAS-driven LUAD, and are associated with poor patient prognosis and outcomes. KEAP1 loss of function (LOF) triggers stabilization of the transcription factor NRF2 which leads to dramatic metabolic and antioxidant reprogramming that confers proliferative and survival advantages to tumor cells. However, these selective advantages also confer targetable metabolic dependencies which arise specifically in the context of KEAP1/NRF2 mutations. The enrichment of these mutations in LUAD carrying undefined or untargetable driver mutations makes unmasking therapeutic vulnerabilities particularly urgent. Identifying metabolic liabilities within KRAS-mutant LUAD would enable the application of precision medicine for the improvement of patient outcomes. In this proposal, I present findings which suggest Keap1-mutant tumors show increased sensitivity to disruption of heme synthesis and that this phenotype is due to Nrf2 activation. I outline my proposed approach to interrogate the metabolic and genetic underpinnings of this apparent vulnerability. I then describe how I will assess if this pathway shows potential for targeted therapy in preclinical models of Kras-driven LUAD including the use of genetically engineered mouse models of LUAD. Hypomorphic mutations in nearly all heme synthesis enzymes have been reported to cause some form hereditary hepatic porphyria. Despite the potential severity of these diseases, their existence among the general population, including healthy adults, provides evidence for the existence of a therapeutic window for heme synthesis inhibition for the treatment of cancer. This fellowship application aims to uncover a novel metabolic target in this genetic subtype of LUAD and will yield a better understanding of a fundamental, yet understudied, metabolic pathway in the development of lung cancer.

项目摘要 KRAS驱动的肺腺癌（LUAD）代表主要的非小细胞肺癌（NSCLC） 治疗方案仍然有限的遗传亚型。 KEAP1/NRF2信号通路中的突变 是几种固体癌症中的常见事件 预后和结果。 KEAP1功能丧失（LOF）触发转录因子NRF2的稳定 这导致了戏剧性的代谢和抗氧化剂重编程，从而赋予增殖和生存 肿瘤细胞的优势。但是，这些选择性优势也赋予了目标代谢依赖性 这是在KEAP1/NRF2突变的背景下特别出现的。这些突变在luad中的富集 携带不确定或不可定制的驾驶员突变会使治疗脆弱性尤其是 紧迫的。确定KRAS突变卢德中的代谢负债将使精确应用 改善患者预后的药物。 在此提案中，我提出的发现表明Keap1突变肿瘤显示出对 血红素合成的破坏，并且该表型是由于NRF2激活引起的。我概述了我建议的方法 询问这种明显脆弱性的代谢和遗传基础。然后我描述我将如何 评估该途径是否显示了针对KRAS驱动的LUAD的临床前模型的靶向治疗的潜力 LUAD的基因工程小鼠模型的使用。 据报道，几乎所有血红素合成酶中的低形态突变都会引起某种形式 遗传性肝斑岩。尽管这些疾病的潜在严重程度，但它们在一般中存在 人口，包括健康的成年人，为存在治疗窗口的血红素提供了证据 对癌症治疗的合成抑制作用。该奖学金申请旨在发现一种新型代谢 目标是luad的这种遗传亚型，将对基本但经过研究的基本，却有更好的理解 肺癌发展中的代谢途径。