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Metabolic Adaptive Responses in Cancer

癌症的代谢适应性反应

基本信息

批准号：
8504876
负责人：
David R Plas
金额：
$ 42.77万
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/8504876
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）：癌症中的代谢适应反应。致癌突变改变信号通路，驱动代谢通路，满足肿瘤细胞生长和抵抗细胞死亡的生物能量和生物合成需求。核糖体蛋白S6激酶1 （S6K1）支持糖酵解下游的致癌突变，以支持生长和生存。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非常敏感。我们最近研究了S6K1作为白血病细胞中减少细胞糖酵解的靶点。S6K1失活后糖酵解的减少只会引起Pten缺失转化的细胞死亡。其他表达BCR-ABL癌基因的白血病细胞在缺乏S6K1信号的情况下适应糖酵解减少，启动代谢适应性反应（MAR），在S6K1失活的情况下介导癌细胞存活。我们在这里表明，BCR-ABL细胞激活脂肪酸氧化（FAO）以响应S6K1的损失。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，我们能够显著提高靶向S6K1和mTORC1的抑制剂的潜在治疗效果。本应用程序中的实验重点是确定S6K1调控的mar的分子机制和功能影响。使用代谢组学，我们将描述响应S6K1活性的精确粮农组织代谢途径。此外，我们将测试S6K1 BCR-ABL下游的特定信号介质在介导MAR中的作用。自噬代谢是一个MAR程序，与FAO一起，已知可以防止对mTORC1抑制剂的细胞毒性反应。我们将在这里测试与靶向mTORC1相比，靶向S6K1是否能规避自噬代谢。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，并将为开发针对癌细胞中S6K1和FAO代谢适应性反应的疗法提供实验框架。