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Targeting metabolic stress to induce pancreatic tumor cell death

针对代谢应激诱导胰腺肿瘤细胞死亡

基本信息

批准号：
10408692
负责人：
Costas Andreas Lyssiotis
金额：
$ 38.42万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408692
关键词：
3-Dimensional Anabolism Apoptosis Biological Assay Cancer Etiology Carbon Cause of Death Cell Death Cells Cessation of life Chemicals Clinical Treatment Cysteine Cysteine Metabolism Pathway Data Dependence Diet Disease Drug Targeting Environment Enzymes Equilibrium Exhibits Fibroblasts Foundations Genetic Genetic Models Genetic Techniques Glutamates Glutathione Growth Human Immunotherapy Impairment In Vitro Incidence Iron Knock-out Lipid Peroxidation Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Metabolic Metabolic Pathway Metabolic stress Metabolism Methods Modeling Mutation NADP Nutrient Oxaloacetates Oxidation-Reduction Oxides Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pre-Clinical Model Process Property Reactive Oxygen Species Regulation Research Proposals Resistance Role Safety Stress Sulfur Survival Rate Techniques Testing Therapeutic Transaminases Translations Treatment Efficacy Tumor-Derived United States base cancer cell effective therapy experimental study extracellular in vivo inhibitor insight interest knock-down metabolomics mitochondrial metabolism mouse model new therapeutic target novel therapeutic intervention pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm programs stable isotope stressor targeted treatment three dimensional cell culture translational potential tumor tumor growth uptake

项目摘要

ABSTRACT Pancreatic cancer is a devastating disease with a five-year survival rate below 10%. One of the main factors underscoring this low survival rate is the lack of effective clinical treatments. Like most cancers, metabolic processes in pancreatic cancer cells are altered to facilitate macromolecular biosynthesis and protect against intra and extracellular stressors. Reactive oxygen species (ROS) are a byproduct of metabolism and represent a notable metabolic stress to pancreatic cancer cells. Previously, we described a new metabolic pathway in pancreatic cancer, mediated by cytosolic glutamate oxaloacetate transaminase 1 (GOT1), that is used to manage ROS by facilitating the coordination of cytosolic and mitochondrial metabolism and maintaining glutathione (GSH) pools. Ferroptosis is a recently described form of iron-dependent, non-apoptotic cell death caused by lipid peroxidation and mediated by loss of GSH pools. We found that GOT1 inhibition potentiated the activity of known ferroptotic agents. Further, we also discovered that GOT1 inhibition can engage ferroptosis when nodes in cysteine metabolism are inhibited. In this research proposal, we will determine how GOT1 inhibition promotes ferroptosis. Mechanistic insight from these studies will then be used to selectively target pancreatic cancers for ferroptotic cell death. This will be accomplished using metabolomics techniques in combination with genetic and pharmacological inhibitors of metabolism. In parallel, we will test combinations of ferroptotic agents with GOT1 inhibition in human patient-derived 3D culture models and in orthotopic mouse models to determine the translation value. Given the safety profile of GOT1 and some ferroptosis-inducers, the profound sensitivity of this combination in pancreatic cancer cells, and the desperate need for new strategies to treat pancreatic cancer, there is now a critical need to understand mechanistically what confers sensitivity to these combinations. Such insights may provide strategies to promote redox imbalance in pancreatic cancer, paving the way for tumor-selective, ferroptosis-based therapies.

摘要胰腺癌是一种毁灭性的疾病，五年生存率低于10%。的主要因素之一由于缺乏有效的临床治疗方法，像大多数癌症一样，代谢性胰腺癌细胞中的过程被改变，以促进大分子生物合成，细胞内和细胞外应激源。活性氧物质（ROS）是代谢的副产物，代表了对胰腺癌细胞有显著的代谢应激。以前，我们描述了一种新的代谢途径，胰腺癌，由细胞溶质谷氨酸草酰乙酸转氨酶1（GOT1）介导，用于通过促进细胞溶质和线粒体代谢的协调来管理ROS，谷胱甘肽（GSH）池。铁凋亡是最近描述的一种铁依赖性、非凋亡性细胞死亡形式，由脂质过氧化引起。过氧化和介导的损失GSH池。我们发现GOT1抑制增强了已知的铁中毒剂。此外，我们还发现，GOT1抑制可以参与铁凋亡时，节点半胱氨酸代谢受到抑制。在这项研究中，我们将确定GOT1抑制促进铁下垂。这些研究的机制见解将用于选择性靶向胰腺癌。铁凋亡细胞死亡的癌症。这将通过代谢组学技术与基因和药物代谢抑制剂。与此同时，我们将测试铁蛋白在人类患者来源的3D培养模型和原位小鼠模型中，确定翻译值。考虑到GOT1和一些铁中毒诱导剂的安全性，这种组合在胰腺癌细胞中的敏感性，以及迫切需要新的治疗策略胰腺癌，现在有一个关键的需要，以了解机制是什么赋予敏感性，这些组合。这些见解可能提供促进胰腺癌氧化还原失衡的策略，肿瘤选择性，铁蛋白沉积为基础的治疗方法。