Overcoming cisplatin resistance by targeting fatty acid metabolism

通过靶向脂肪酸代谢克服顺铂耐药性

基本信息

批准号：
9980866
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980866
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

项目摘要

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.

抽象的化疗是减少局部复发和远处转移的关键工具晚期口腔鳞状细胞癌（OCSCC）患者虽然是老药，自此，顺铂成为美国 OCSCC 化疗方案的支柱。 OCSCC 顺铂反应变化很大，开发新的克服方法至关重要顺铂耐药性的获得是 OCSCC 生存的关键驱动因素。和顺铂耐药性；然而，我们不能直接有效地针对TP53的突变。初步数据表明，靶向脂质代谢可以克服顺铂耐药性与“高风险”TP53 突变相关。突变导致 p53 功能丧失：1) 损害线粒体储备能力，2) 增加糖酵解通量，3) 增加细胞对氧化应激的适应。与顺铂抗性增强同时发生。合成（FAS）是细胞氧化应激反应的关键驱动因素，因为它们负责大部分还原当量（NADH、NADPH、FADH2）的产生和/或在目标 1 中，我们将测试高风险 TP53 突变对 FAO/FAS 比率和利用率的影响。评估FAO抑制剂在改善高危人群顺铂反应方面的相对有效性 TP53突变。在目标 2 中，我们将使用同样基于脂质的 TP53 突变肿瘤的平行方法铁死亡（程序性细胞死亡）由氧化应激和依赖性激活。我们发现铁死亡激动剂可以在两种野生型中引起细胞死亡。和突变 TP53 OCSCC 在这个目标中，我们将测试铁死亡激动剂是否可以克服。顺铂耐药性与细胞系和 PDX 肿瘤中的“高风险”TP53 突变相关。尽管不断寻找更有效的替代品，顺铂仍然是主流直到其他药物证明明确为止。和优势，我们必须制定更有效的战略，这些策略还必须考虑到克服顺铂耐药性。在当前的提案中，我们利用了 TP53 突变对 OCSCC 治疗反应的影响。有关代谢靶向的大量初步数据并建议采用一种方法以脂肪酸代谢为基础，我们相信它解决了这一致命问题的两个方面疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress.

顺铂耐药性的获得使头颈鳞状细胞癌代谢转向氧化应激的中和。

DOI：
发表时间：
2020-06-24
期刊：
影响因子：
5.2
作者：
Yu, Wangjie;Chen, Yunyun;Putluri, Nagireddy;Coarfa, Cristian;Robertson, Matthew J;Putluri, Vasanta;Stossi, Fabio;Dubrulle, Julien;Mancini, Michael A;Pang, Jonathan C;Nguyen, Trung;Baluya, Dodge;Myers, Jeffrey N;Lai, Stephen Y;Sandulache, Vla
通讯作者：
Sandulache, Vla

Using Ligand-Accelerated Catalysis to Repurpose Fluorogenic Reactions for Platinum or Copper.

使用配体加速催化重新利用铂或铜的荧光反应。

DOI：
发表时间：
2020-10-28
期刊：
影响因子：
18.2
作者：
Pham, Dianne;Deter, Carly J;Reinard, Mariah C;Gibson, Gregory A;Kiselyov, Kirill;Yu, Wangjie;Sandulache, Vlad C;St Croix, Claudette M;Koide, Kazunori
通讯作者：
Koide, Kazunori