Overcoming cisplatin resistance by targeting fatty acid metabolism

通过靶向脂肪酸代谢克服顺铂耐药性

• 批准号: 9795719
• 负责人: VLAD C SANDULACHE
• 金额: $ 16.69万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795719
• 关键词: Address; Agonist; Angiogenesis Inhibitors; Apoptosis; Carbon; Carnitine Palmitoyltransferase I; Cell Death; Cell Line; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Data; Disease; Distant Metastasis; Effectiveness; FADH2; Failure; Fatty Acids; Generations; Glycolysis; Impairment; Knowledge; Lipid Peroxidation; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Medicine; Metabolic; Mitochondria; Mutation; NADH; NADP; Oncogenes; Oxidative Stress; Patients; Pharmaceutical Preparations; RAS genes; Recurrence; Regimen; Research; Research Personnel; Resistance; Respiration; TP53 gene; Technology; Testing; Time; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; United States; Vertebral column; World Health Organization; base; biological adaptation to stress; chemotherapy; clinical practice; fatty acid metabolism; fatty acid oxidation; high risk; improved; inhibitor/antagonist; lipid metabolism; liquid chromatography mass spectrometry; malignant mouth neoplasm; mouth squamous cell carcinoma; mutant; mutational status; neoplastic cell; novel; novel strategies; relative effectiveness; response; standard of care; targeted agent; tool; treatment response; tumor; tumor metabolism

ABSTRACT Chemotherapy is a critical tool in reducing locoregional recurrence and distant metastasis in patients with advanced oral cavity squamous cell carcinoma (OCSCC). Although an old drug, cisplatin forms the backbone of chemotherapy regimens for OCSCC in the United States. Since OCSCC cisplatin response is highly variable, it is critical to develop novel means of overcoming cisplatin resistance. Acquisition of “high-risk” TP53 mutations is a critical driver of OCSCC survival and cisplatin resistance; however, mutations of TP53 cannot be effectively targeted directly. Our preliminary data indicate, that targeting of lipid metabolism, could overcome cisplatin resistance associated with “high-risk” TP53 mutations. Loss of p53 function through mutation: 1) impairs mitochondrial reserve capacity, 2) increases glycolytic flux and 3) increases cellular adaptation to oxidative stress. These effects occur in parallel with enhanced resistance to cisplatin. Fatty acid oxidation (FAO) and fatty acid synthesis (FAS) are critical drivers of the cellular oxidative stress response since they are responsible for a large portion of reducing equivalent (NADH, NADPH, FADH2) generation and/or utilization. In Aim 1 we will test the impact of high-risk TP53 mutations on the FAO/FAS ratio and evaluate the relative effectiveness of FAO inhibitors in improving cisplatin response in high-risk TP53 mutations. In Aim 2 we will use a parallel approach to TP53 mutant tumors also predicated on lipid metabolism. Ferroptosis (programmed cell death) is activated by oxidative stress and dependent on lipid peroxidation. We found that ferroptosis agonists can generate cell death in both wild-type and mutant TP53 OCSCC. In this Aim we will test whether ferroptosis agonists can overcome cisplatin resistance associated with “high-risk” TP53 mutations in cell lines and PDX tumors. Despite a continued search for more effective alternatives, cisplatin remains the mainstay systemic agent for use in advanced OCSCC. Until such time as other agents demonstrate clear and convincing superiority, it is imperative that we develop more effective strategies which can overcome cisplatin resistance. These strategies must also take into account the overwhelming impact of TP53 mutations on OCSCC response to treatment. In the current proposal, we leverage substantial preliminary data regarding metabolic targeting and propose to utilize an approach predicated on fatty acid metabolism which we believe addresses both aspects of this deadly disease.

抽象的 化学疗法是减少局部复发和远处转移的关键工具 患有晚期口腔鳞状细胞癌（OCSCC）的患者。虽然是一种旧药物， 顺铂构成了美国OCSCC化学疗法方案的骨干。自从 OCSCC顺铂反应是高度可变的，开发新颖的克服手段至关重要 顺铂耐药性。获得“高风险” TP53突变是OCSCC生存的关键驱动力 和顺铂耐药性；但是，TP53的突变不能直接靶向。我们的 初步数据表明，靶向脂质代谢可以克服顺铂抗性 与“高风险” TP53突变有关。 通过突变丧失p53功能：1）损害线粒体储备的容量，2） 增加糖酵解通量和3）增加了细胞对氧化应激的适应性。这些影响 并行与对顺铂的抗性增强。脂肪酸氧化（FAO）和脂肪酸 合成（FAS）是细胞氧化物应激反应的关键驱动因素，因为它们是 负责大部分减少同等（NADH，NADPH，FADH2）生成和/或 利用率。在AIM 1中，我们将测试高风险TP53突变对粮农组织/FAS比的影响 评估粮农 TP53突变。 在AIM 2中，我们将使用平行的方法对TP53突变肿瘤进行脂质预测 代谢。氧化应激和依赖性氧化性毒性（程序性细胞死亡）被激活 关于脂质过氧化。我们发现，铁毒性激动剂可以在两种野生型中产生细胞死亡 和突变体TP53 OCSCC。在此目的中，我们将测试铁毒性激动剂是否可以克服 与细胞系和PDX肿瘤中“高风险” TP53突变相关的顺铂耐药性。 尽管继续寻找更有效的替代方案，但顺铂仍然是中流tay 用于高级OCSCC的系统性代理。直到其他代理商表现出清晰的时间 并令人信服的优势，我们必须制定更有效的策略 克服顺铂耐药性。这些策略还必须考虑到压倒性的 TP53突变对OCSCC对治疗反应的影响。在当前的建议中，我们利用 有关代谢靶向和提议的大量初步数据，以利用一种方法 以脂肪酸代谢为基础 疾病。