Metabolic Regulators of Tumor Cell Growth

肿瘤细胞生长的代谢调节剂

基本信息

批准号：
8657905
负责人：
RALPH J DEBERARDINIS
金额：
$ 32万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657905
关键词：
Address Adult Amino Acids Animal Cancer Model Biological Brain Carbon Cell Line Cell Proliferation Cell division Cells Citrates Cultured Cells Disease EGFR Gene Amplification Enzymes Epidermal Growth Factor Receptor Explosion Foundations Genetic Glioblastoma Glioma Glucose Glutamine Glycolysis Growth Human In Vitro Label Lead Life Lipids Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Measurement Measures Metabolic Metabolic Pathway Metabolism Methods Mitochondria Molecular Mus Mutation NMR Spectroscopy Nature Neuraxis Nuclear Magnetic Resonance Nucleic Acids Nutrient PTEN gene Pathway interactions Patients Phenotype Phosphatidylinositols Phosphotransferases Process Production Proteins RNA Interference Radiation Resistance Role Signal Transduction Source Testing Time Transplantation Tumor Suppressor Proteins Work Xenograft procedure analytical method cancer therapy cell growth chemotherapy glucose metabolism in vivo killings loss of function macromolecule meetings metabolic abnormality assessment metaplastic cell transformation neoplastic cell new therapeutic target novel novel therapeutic intervention novel therapeutics research study subcutaneous therapeutic target tumor tumor growth tumor metabolism tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most lethal form of brain cancer in adults. Despite a recent explosion of information on the genetic causes of this disease, the average survival of GBM patients is only 15 months and the tumors tend to be resistant to all known therapies. The devastating nature of GBM underscores a dire need for novel therapeutic targets and a better understanding of the molecular mechanisms that drive the growth and maintenance of these tumors. Like other aggressive tumors, GBMs display a high degree of cell proliferation made possible by the activation of a select set of metabolic activities required to generate the energy and macromolecules (lipids, nucleic acids, proteins) needed for cell growth and division. These metabolic activities are attractive therapeutic targets because they lie between the diverse molecular drivers of cellular transformation in GBM and the phenotype of rapid tumor growth that ultimately kills the patient. The main objective of this proposal is to define the metabolic regulators of GBM cell growth in vitro and in vivo. The proposal builds on our novel analytical methods developed to measure metabolism of GBM cells in culture and, for the first time, in intact human GBM tumors grown in the mouse. These methods led to the surprising observation that GBM cells have highly active mitochondria that use either of two metabolic pathways to convert nutrients into precursors required for macromolecular synthesis and growth. Specific Aim 1 proposes loss-of-function experiments with RNA interference to identify key metabolic regulators that allow GBM cells to use the amino acid glutamine as the preferred mitochondrial substrate. Specific Aim 2 proposes similar experiments to define the key metabolic regulators in an alternative metabolic pathway that does not require glutamine but still allows tumor cells to grow rapidly in culture and in vivo. Specific Aim 3 proposes to study metabolism in twenty independent human GBM tumors grown exclusively in the mouse brain to understand how tumor mutations influence metabolic activity, and whether particular mutations define sensitivity to the suppression of metabolic activities in vivo. All three Specific Aims feature extensive metabolic analysis of live tumors using nuclear magnetic resonance spectroscopy and mass spectrometry, and will produce a unique view of GBM metabolism with an unprecedented level of detail and biological accuracy. Together, these experiments will pinpoint a new set of metabolic activities that distinguish GBM tumors from normal brain, will define mechanisms that connect malignant transformation to cellular metabolism, and will identify metabolic targets that should lead to novel therapeutic approaches in GBM and potentially other aggressive cancers.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人中最致命的脑癌。尽管最近关于这种疾病的遗传原因的信息激增，但 GBM 患者的平均生存期仅为 15 个月，而且肿瘤往往对所有已知的疗法都有抵抗力。 GBM 的破坏性本质强调了对新治疗靶点的迫切需要以及对驱动这些肿瘤生长和维持的分子机制的更好理解。与其他侵袭性肿瘤一样，GBM 表现出高度的细胞增殖，这是通过激活一组选定的代谢活动来产生细胞生长和分裂所需的能量和大分子（脂质、核酸、蛋白质）而实现的。这些代谢活动是有吸引力的治疗靶点，因为它们位于 GBM 细胞转化的多种分子驱动因素和最终杀死患者的肿瘤快速生长的表型之间。该提案的主要目的是确定 GBM 细胞体外和体内生长的代谢调节因子。该提案建立在我们开发的新颖分析方法的基础上，该方法旨在测量培养物中 GBM 细胞的代谢，并首次测量在小鼠中生长的完整人类 GBM 肿瘤中的代谢。这些方法令人惊讶地发现，GBM 细胞具有高度活跃的线粒体，它们使用两种代谢途径中的任何一种将营养物质转化为大分子合成和生长所需的前体。具体目标 1 提出利用 RNA 干扰进行功能丧失实验，以确定关键的代谢调节因子，使 GBM 细胞能够使用氨基酸谷氨酰胺作为首选线粒体底物。具体目标 2 提出了类似的实验来定义替代代谢途径中的关键代谢调节因子，该途径不需要谷氨酰胺，但仍允许肿瘤细胞在培养物和体内快速生长。具体目标 3 提议研究仅在小鼠大脑中生长的 20 个独立的人类 GBM 肿瘤的代谢，以了解肿瘤突变如何影响代谢活动，以及特定突变是否定义了对体内代谢活动抑制的敏感性。所有三个具体目标均采用核磁共振波谱法和质谱法对活体肿瘤进行广泛的代谢分析，并将产生具有前所未有的详细程度和生物学准确性的 GBM 代谢的独特视图。总之，这些实验将查明一组新的代谢活动，将 GBM 肿瘤与正常大脑区分开来，将定义将恶性转化与细胞代谢联系起来的机制，并将确定代谢目标，从而为 GBM 和潜在的其他侵袭性癌症带来新的治疗方法。