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）：多形胶质母细胞瘤（GBM）是成年人最致命的脑癌形式。尽管最近关于该疾病遗传原因的信息发生了爆炸，但GBM患者的平均存活率仅为15个月，肿瘤往往对所有已知疗法具有抗性。 GBM的破坏性强调了对新型治疗靶标的迫切需求，并更好地理解了推动这些肿瘤生长和维持的分子机制。与其他侵袭性肿瘤一样，GBM显示出高度的细胞增殖，通过激活一组生成能量和大分子所需的代谢活性（脂质，核酸，蛋白质）所需的代谢活性。这些代谢活性是有吸引力的治疗靶标，因为它们位于GBM中细胞转化的各种分子驱动因素与最终杀死患者的快速肿瘤生长的表型之间。该提案的主要目的是定义体外和体内GBM细胞生长的代谢调节剂。该提案建立在我们开发的新型分析方法的基础上，旨在测量培养物中GBM细胞的代谢，并首次在小鼠中生长的完整人类GBM肿瘤。这些方法导致了令人惊讶的观察结果，即GBM细胞具有高度活性的线粒体，该线粒体使用两种代谢途径中的任何一个将养分转化为大分子合成和生长所需的前体。特定目标1提出了对RNA干扰的功能丧失实验，以识别允许GBM细胞使用氨基酸谷氨酰胺作为首选线粒体底物的关键代谢调节剂。具体目标2提出了类似的实验，以在不需要谷氨酰胺但仍允许肿瘤细胞在培养和体内迅速生长的替代代谢途径中定义关键的代谢调节剂。具体目标3提出，研究仅在小鼠脑中种植的二十种独立的人类GBM肿瘤中的代谢，以了解肿瘤突变如何影响代谢活性，以及特定突变是否定义了对体内代谢活性抑制的敏感性。所有三个特定的目标均使用核磁共振光谱和质谱法对活肿瘤进行广泛的代谢分析，并将产生GBM代谢的独特视图，并具有前所未有的细节和生物学准确性。总之，这些实验将确定一组新的代谢活性，这些新代谢活性将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，并将确定应该导致GBM中新型治疗方法的代谢靶标的机制。