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：
10656461
负责人：
Costas Andreas Lyssiotis
金额：
$ 38.31万
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/10656461
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 Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy 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 United States 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 pharmacologic programs protective pathway stable isotope stressor 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.

抽象的胰腺癌是一种毁灭性疾病，五年生存率低于 10%。主要因素之一缺乏有效的临床治疗凸显了这种低生存率。与大多数癌症一样，代谢胰腺癌细胞中的过程被改变以促进大分子生物合成并防止细胞内和细胞外的应激源。活性氧 (ROS) 是新陈代谢的副产品，代表对胰腺癌细胞产生显着的代谢应激。之前，我们描述了一种新的代谢途径胰腺癌，由胞质谷氨酸草酰乙酸转氨酶 1 (GOT1) 介导，用于通过促进细胞质和线粒体代谢的协调并维持谷胱甘肽 (GSH) 库。铁死亡是最近描述的一种由脂质引起的铁依赖性非凋亡细胞死亡形式过氧化反应是由 GSH 池的损失介导的。我们发现 GOT1 抑制增强了已知的铁死亡剂。此外，我们还发现，当节点半胱氨酸代谢受到抑制。在本研究计划中，我们将确定如何抑制 GOT1 促进铁死亡。这些研究的机制见解将用于选择性地靶向胰腺癌症导致铁死亡细胞。这将通过结合代谢组学技术来完成具有代谢的遗传和药理学抑制剂。同时，我们将测试铁死亡的组合在人类患者衍生的 3D 培养模型和原位小鼠模型中具有 GOT1 抑制作用的药物确定翻译值。鉴于 GOT1 和一些铁死亡诱导剂的安全性，深刻的研究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，现在迫切需要从机制上了解是什么赋予了对这些癌症的敏感性组合。这些见解可能提供促进胰腺癌氧化还原失衡的策略，铺平道路肿瘤选择性、基于铁死亡的治疗方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.

DOI：
10.1101/gad.344184.120
发表时间：
2021-02-01
期刊：
Genes & development
影响因子：
10.5
作者：
Purohit V;Wang L;Yang H;Li J;Ney GM;Gumkowski ER;Vaidya AJ;Wang A;Bhardwaj A;Zhao E;Dolgalev I;Zamperone A;Abel EV;Magliano MPD;Crawford HC;Diolaiti D;Papagiannakopoulos TY;Lyssiotis CA;Simeone DM
通讯作者：
Simeone DM

Clinical Targeting of Altered Metabolism in High-Grade Glioma.