Triggering a New Cancer Cell Death Mechanism in Sarcoma

触发肉瘤中新的癌细胞死亡机制

• 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
• 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

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的细胞死亡的有力工具 可能对癌症治疗有用的机制。利用小分子，我们已经发现 一种不同于凋亡的非凋亡性细胞死亡的非常规形式，铁凋亡， 以及其他已知的细胞死亡形式。这种致死机制需要蛋白质棕榈酰化， 包括破坏蛋白质运输。在这项研究中，我们建议测试脂质的作用， 可能积极或消极地调节眼睑下垂的代谢酶。其中一个目的 研究将集中在脂质代谢酶TECR（反式-2，3-烯酰辅酶A还原酶）上。我们 将测试TECR合成棕榈酸的假设，棕榈酸用于蛋白质棕榈酰化 酶通过改变蛋白质运输来驱动细胞死亡。本研究的第二个目的是测试 细胞死亡是由磷脂酰胆碱代谢的破坏引发的假设， 从而改变蛋白质运输。本研究的第三个目的是检验这一新的假设， 细胞死亡机制可以在癌症的基因工程小鼠模型中通过 临床候选药物虽然这种细胞死亡机制可以在多种癌症中被激活，但 拟议研究的主要重点是肉瘤，这是高度敏感的致命 这是一种机制，迫切需要新的治疗方法。这些研究将 定义了一种新的细胞死亡形式和相关的生化机制， 用于治疗肉瘤和其他癌症。