Metabolic Control and Anticancer Mechanism

代谢控制与抗癌机制

• 批准号: 10373070
• 负责人: STEVEN ZHENG
• 金额: $ 33.43万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373070
• 关键词: Antineoplastic Agents; Biogenesis; CCI-779; Clinical; Data; Drug Targeting; Event; FDA approved; Genes; Genetic Transcription; Growth; Human; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolism; Mutate; Nuclear; Nutrient; Oncogenic; Oncology; Oxidative Phosphorylation; Oxygen; Pathway interactions; Pharmaceutical Preparations; Process; RNA Splicing; RNA-Binding Proteins; Regulation; Signal Transduction; Sirolimus; Stimulus; Structure; Testing; Untranslated RNA; Warburg Effect; aerobic glycolysis; anti-cancer; cancer cell; cell growth; improved outcome; inhibitor; insight; mRNA Precursor; polymerization; response; targeted treatment; treatment response; tumor metabolism; tumorigenesis; tumorigenic

ABSTRACT As a central controller of cancer growth and metabolism, mTORC1 pathway is commonly mutated and activated in human cancer, leading to uncontrolled growth. Cancer cells are ‘addicted’ to elevated mTORC1 signaling, rendering mTORC1 a desirable cancer drug target. The highly specific mTORC1 inhibitors rapamycin analogs (rapalogs, e.g. temsirolimus) are US FDA-approved oncology drugs. However, their clinical response has been moderate, which is in a large part due to incomplete understanding of mTORC1 signaling mechanisms underpinning rapamycin action. In this application, we will test the central hypothesis that nuclear mTORC1 signaling promotes aerobic glycolysis, or Warburg Effect, through a long non-coding RNA (lncRNA) NEAT1- dependent mechanism, which is important for mTORC1-driven tumorigenesis and rapamycin response. A successful completion of this project will provide a deeper understanding of this oncogenic pathway and therapeutic response to its blockage.

抽象的 作为癌症生长和代谢的中央控制者，mTORC1 通路通常会发生突变和激活 在人类癌症中，导致癌细胞对 mTORC1 信号传导“上瘾”， 使 mTORC1 成为理想的癌症药物靶点。高度特异性的 mTORC1 抑制剂雷帕霉素类似物。 （rapalogs，例如替西罗莫司）是美国 FDA 批准的肿瘤药物，但其临床反应却不佳。 中等，这很大程度上是由于对mTORC1信号机制理解不完全造成的 在本申请中，我们将测试核 mTORC1 的中心假设。 信号传导通过长非编码 RNA (lncRNA) NEAT1- 促进有氧糖酵解或 Warburg 效应 依赖机制，这对于 mTORC1 驱动的肿瘤发生和雷帕霉素 A 反应很重要。 该项目的成功完成将加深对这一致癌途径的了解， 对其阻断的治疗反应。