Triggering a New Cancer Cell Death Mechanism in Sarcoma

触发肉瘤中新的癌细胞死亡机制

基本信息

批准号：
10735740
负责人：
Scott Dixon
金额：
$ 45.84万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735740
关键词：
Acyltransferase Aggressive Fibromatosis Animal Cancer Model Animal Model Antineoplastic Agents Apoptosis Apoptotic Biochemical Cancer Model Caspase Cell Death Cell Death Induction Cell Line Clinical Clinical Research Clinical Treatment Clinical Trials Coenzyme A Connective Tissue Elements Enzymes Fatty Acids Future Genes Genetic Screening Genetically Engineered Mouse Goals Human Image Investigation Lecithin Link Lipids Lysophospholipids Malignant Neoplasms Mesenchymal Cell Neoplasm Metabolic Metabolism Modeling NF-kappa B Names Oxidoreductase Palmitates Palmitoyl Coenzyme A Pathway interactions Patients Post-Translational Protein Processing Proteins Regulation Research Resistance Role Soft tissue sarcoma Testing Therapeutic Therapeutic Effect Toxic effect Tumor Suppressor Proteins analog cancer cell cancer therapy cell type conventional therapy design drug candidate genome-wide improved outcome in vivo innovation interest lipid metabolism lipidomics molecular marker novel novel strategies novel therapeutic intervention novel therapeutics palmitoylation protein transport sarcoma small molecule targeted cancer therapy therapeutic target tool

项目摘要

Project Abstract Lethal small molecules are powerful tools to discover and characterize new cell death mechanisms that may be useful for cancer treatment. Using small molecules, we have identified an unconventional form of non-apoptotic cell death that is distinct from apoptosis, ferroptosis, and other known forms of cell death. This lethal mechanism requires protein palmitoylation and involves the disruption of protein trafficking. In this research we propose to test the role of lipid metabolic enzymes that may positively or negatively regulate palmoptosis. One Aim of this research will focus on the lipid metabolic enzyme TECR (trans-2,3-enoyl-CoA reductase). We will test the hypothesis that TECR synthesizes palmitate that is used by protein palmitoylation enzymes to drive cell death via altered protein trafficking. A second Aim of this research will test the hypothesis that cell death is triggered by the disruption of phosphatidylcholine metabolism, which alters protein trafficking. A third Aim of this research will test the hypothesis that this new cell death mechanism can be activated in genetically engineered mouse models of cancer by a clinical drug candidate. While this cell death mechanism can be activated in diverse cancers, a major focus of the proposed studies is on sarcoma, which is highly sensitive to this lethal mechanism and for which new treatments are urgently needed. Together, these studies will define a new form of cell death and associated biochemical mechanisms that may be exploited for the treatment of sarcoma and other cancers.

项目摘要致命的小分子是发现和表征新细胞死亡的强大工具可能对癌症治疗有用的机制。使用小分子，我们已经确定了非凋亡细胞死亡的一种非常规的形式，与凋亡，铁凋亡，和其他已知形式的细胞死亡形式。这种致命的机制需要蛋白质棕榈酰化和涉及蛋白质运输的破坏。在这项研究中，我们建议测试脂质的作用代谢酶可能会阳性或负调节手掌作用。一个目的研究将重点放在脂质代谢酶TECR（Trans-2,3-烯酰基-COA还原酶）上。我们将检验以下假设：TECR合成棕榈酸使用的棕榈酸酯酶通过改变蛋白质运输来驱动细胞死亡。这项研究的第二个目标将测试磷脂酰胆碱代谢的破坏引发了细胞死亡的假设，这改变了蛋白质运输。这项研究的第三个目标将检验以下假设细胞死亡机制可以在基因工程的癌症模型中通过A激活临床药物候选人。尽管这种细胞死亡机制可以在不同的癌症中激活拟议的研究的主要重点是肉瘤，这对这种致命高度敏感机制以及迫切需要新的治疗方法。这些研究将在一起定义一种可能被利用的新形式的细胞死亡和相关的生化机制用于治疗肉瘤和其他癌症。