Metabolic Adaptive Responses in Cancer

癌症的代谢适应性反应

基本信息

批准号：
8626366
负责人：
David R Plas
金额：
$ 41.21万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8626366
关键词：
1-Phosphatidylinositol 3-Kinase Autophagocytosis Bioenergetics Cell Death Cell Survival Cells Cessation of life Chemotherapy-Oncologic Procedure Clinical Trials Complex Data FDA approved Fatty Acids Feedback Glucose Glycolysis Growth Interruption Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Molecular Mutation Myeloproliferative disease Neoplasms Oncogenes Oncogenic Pathway interactions Pharmaceutical Preparations Publications Regulation Research Research Proposals Resistance Resistance development Ribosomal Protein S6 Kinase Role Signal Pathway Signal Transduction Sirolimus Supporting Cell Testing Therapeutic Treatment Efficacy Tumor Suppressor Genes Work aerobic glycolysis analog bcr-abl Fusion Proteins cancer cell cancer therapy cell growth cell transformation chemotherapy cytotoxic fatty acid oxidation fatty acid transport frontier glucose metabolism human FRAP1 protein in vivo in vivo Model inhibitor/antagonist leukemia leukemogenesis mTOR Inhibitor macromolecule malignant breast neoplasm meetings metabolomics mouse model neoplastic cell next generation novel pre-clinical prevent programs public health relevance research study response ribosomal protein S6 kinase 1 therapeutic development therapy development upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Metabolic adaptive responses in cancer. Project Summary Oncogenic mutations alter signaling pathways to drive metabolic pathways that meet the bioenergetic and biosynthetic demands of increased tumor cell growth and resistance to cell death. The ribosomal protein S6 kinase 1 (S6K1) supports glycolysis downstream of oncogenic mutations to support growth and survival. Increased glycolysis renders cells "addicted" to glucose metabolism, and cells are consequently hypersensitive to interruptions in glycolytic metabolism. We recently investigated S6K1 as a target for reducing cellular glycolysis in leukemia cells. Decreased glycolysis upon S6K1 inactivation triggered cell death only cells that were transformed by loss of Pten. Other leukemia cells expressing the BCR-ABL oncogene adapted to decreased glycolysis in the absence of S6K1 signaling, initiating a Metabolic Adaptive Response, or MAR, to mediate cancer cell survival despite S6K1 inactivation. We show here that BCR-ABL cells activate fatty acid oxidation (FAO) in response to loss of S6K1. Treatment of cells with a FAO inhibitor enhanced the cytotoxic responses of BCR-ABL+ cells to S6K1 inactivation or mTORC1 inactivation. Thus, by understanding and targeting the MAR in leukemia cells, we were able to dramatically enhance the potential therapeutic efficacy of inhibitors targeting S6K1 and mTORC1. Experiments in this application are focused on determining the molecular mechanisms and functional impact of the S6K1-regulated MAR. Using metabolomics, we will delineate the precise FAO metabolic pathways that respond to S6K1 activity. In addition, we will test specific signaling mediators downstream of S6K1 BCR-ABL for their role in mediating the MAR. Autophagic metabolism is a MAR program that, along with FAO, is known to prevent cytotoxic responses to mTORC1 inhibitors. We will test here whether targeting S6K1 circumvents autophagic metabolism compared to targeting mTORC1. Finally, we will develop in vivo models of leukemia that will allow us to specifically test the contributions of S6K1-glycolysis and the FAO-MAR on leukemogenesis and therapeutic response. The project combines mechanistic analysis of metabolism and signal transduction with translational analysis of functional impact, and will yield the experimental framework for developing therapies that target S6K1 and the FAO Metabolic Adaptive Response in cancer cells.

描述（由申请人提供）：癌症中的代谢适应性反应。项目摘要致癌突变改变信号传导途径，以驱动代谢途径，满足肿瘤细胞生长增加和细胞死亡抵抗力的生物能和生物合成需求。核糖体蛋白 S6 激酶 1 (S6K1) 支持致癌突变下游的糖酵解，以支持生长和存活。糖酵解的增加使细胞对葡萄糖代谢“上瘾”，因此细胞对糖酵解代谢的中断高度敏感。我们最近研究了 S6K1 作为减少白血病细胞糖酵解的靶标。 S6K1 失活后糖酵解的减少仅引发因 Pten 缺失而转化的细胞死亡。其他表达 BCR-ABL 癌基因的白血病细胞在缺乏 S6K1 信号传导的情况下适应糖酵解减少，启动代谢适应性反应 (MAR)，以介导癌细胞在 S6K1 失活的情况下存活。我们在此表明，BCR-ABL 细胞响应 S6K1 的丢失而激活脂肪酸氧化 (FAO)。用FAO抑制剂处理细胞增强了BCR-ABL+细胞对S6K1失活或mTORC1失活的细胞毒性反应。因此，通过了解和靶向白血病细胞中的 MAR，我们能够显着增强针对 S6K1 和 mTORC1 的抑制剂的潜在治疗功效。本应用中的实验重点是确定 S6K1 调节的 MAR 的分子机制和功能影响。利用代谢组学，我们将描绘出响应 S6K1 活性的精确 FAO 代谢途径。此外，我们将测试 S6K1 BCR-ABL 下游的特定信号传导介质在介导 MAR 中的作用。自噬代谢是一项 MAR 计划，与 FAO 一起，已知可以防止 mTORC1 抑制剂的细胞毒性反应。我们将在此测试与靶向 mTORC1 相比，靶向 S6K1 是否会规避自噬代谢。最后，我们将开发白血病的体内模型，这将使我们能够专门测试 S6K1 糖酵解和FAO-MAR 对白血病发生和治疗反应的贡献。该项目将代谢和信号转导的机制分析与功能影响的转化分析相结合，并将产生用于开发针对癌细胞中的 S6K1 和 FAO 代谢适应性反应的疗法的实验框架。