Targeting TCA cycle in Brain Tumor Initiating Cells

靶向脑肿瘤起始细胞中的 TCA 循环

基本信息

批准号：
9263682
负责人：
Jin Young Kim
金额：
$ 0.64万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263682
关键词：
Acetylation Aerobic Affinity Amino Acids Anabolism Angiogenesis Inhibitors Animals Apoptosis Biopsy Blood Vessels Brain Brain Diseases Brain Glioblastoma Brain Neoplasms Brain Stem Cancer Cell Growth Carbon Cell Death Cell Survival Cells Citric Acid Cycle Deacetylation Electron Transport Energy Supply Environment Enzymes Epilepsy Foundations GLUT-3 protein Generations Genetic Glioblastoma Glioma Glucose Glucose Transporter Glycolysis Growth Human Impairment Invaded Laboratories Link Malignant - descriptor Malignant Neoplasms Mediating Mentors Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial Proteins Modeling Modification Molecular Molecular Target Natural regeneration Neurons Normal tissue morphology Nutrient Organ Oxidative Phosphorylation Oxygen Patients Pattern Phenocopy Phenotype Post-Translational Protein Processing Post-Translational Regulation Prevalence Primary Brain Neoplasms Process Production Property Protein Acetylation Radiation Radiation therapy Regulation Research Resistance Resources Role Series Sir2-like Deacetylases Source Stem cells Stress Therapeutic Tissues Transplantation Tumor Angiogenesis Tumor Initiators Vertebral column Warburg Effect Work World Health Organization aerobic glycolysis angiogenesis base bevacizumab cancer cell cell growth cell killing chemotherapy conventional therapy cost design empowered extracellular improved innovation macromolecule neoplastic neoplastic cell new therapeutic target novel novel therapeutics nucleotide metabolism preclinical development pressure public health relevance regenerative repaired response self-renewal stem stem-like cell stemness therapeutic target therapy resistant tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The human brain represents one of the most metabolically active organs with a highly efficient ability to extract glucose as the primary currency for energy and carbon source. In particular, neurons are distinguished in their ability to preferentially absorb glucose from a nutrient-restricted environment through the expression of high affinity glucose transporters. The most prevalent primary brain tumor, glioblastoma, ranks among the most lethal of human cancers. Like the normal brain, glioblastomas contain cellular hierarchies with self-renewing, multi-lineage cells at the apex. These brain tumor initiating cells display therapeutic resistance, promote tumor angiogenesis, and invade into normal tissues providing rationale to model their regulation and develop targeting strategies. We recently demonstrated that brain tumor initiating cells display a marked ability to survive the reduced nutrient levels found in the neoplastic brain through the cooption of the neuronal glucose transporter, GLUT3. In contrast, non-stem cell-like tumor cells underwent cell death with nutrient restriction with a cellular plasticity towards a stem cell-like state in surviving cells. Collectivly, these studies identify a novel molecular mechanism associated with the tumor cellular hierarchy that could provide a node of fragility as targeting GLUT3 expression reduced brain tumor initiating cell self-renewal and tumor growth. Like all cancers, glioblastomas display the Warburg effect, a preferential utilization of aerobic glycolysis for energy supplies. This aerobic glycolyss frees the cells from oxygen requirements and provides a steady supply of anabolic material, yet is highly glucose inefficient and requires a steady supply of glucose, suggesting a potential therapeutic target. Based on this background, we hypothesize that preferential use of glucose-derived carbon backbones for macromolecular biosynthesis allows brain tumor initiating cells to survive under extracellular energy stress and provides an ability to these cells to occupy a diverse set of niches with different metabolic limitations. The anti- angiogenic bevacizumab has shown promise in the initial response of tumors to therapy but has failed to extend survival. Studies have suggested that angiogenic inhibitor resistance is associated with impaired vascular function and metabolic shifts that may enrich for tumor initiating cells. To investigate these potential links between cellular metabolism and the tumor hierarchy, we will dissect the interplay between brain tumor initiating cells and the tumor microenvironment. In the first aim, we will determine the role of the stem cell metabolic responses in stress resistance. In the second aim, we will interrogate the role of post-translational modification of mitochondrial proteins in different tumor microenvironments enriched in tumor initiating cells through the use of regional biopsies from human patients and regionally specific SIRT3 modification in animal studies. Finally, we will investigate the potential synthetic lethality of targeting SIRT3 with chemotherapy and/or radiation. We will employ a series of models derived from human glioblastomas and epilepsy tissues to lay the foundation for advanced modeling of this lethal brain disease.

描述（由应用程序提供）：人脑代表了最具代谢活性的器官之一，具有高效的能力，可以提取葡萄糖作为能量和碳源的主要货币。特别是，神经元在其能力方面具有区分最好通过高亲和葡萄糖转运蛋白的表达从营养限制的环境中吸收葡萄糖。最普遍的原发性脑肿瘤，胶质母细胞瘤是最致命的人类癌症之一。像正常的大脑一样，胶质母细胞瘤包含细胞层次结构，并在顶点处具有自我更新，多型细胞。这些脑肿瘤引发了细胞显示理论抗性，促进肿瘤血管生成并入侵正常的肿瘤，提供了对其调节和制定靶向策略进行建模的基本原理。我们最近证明，通过神经元葡萄糖转运蛋白Glut3，脑肿瘤启动细胞具有在肿瘤大脑中发现的降低的养分水平的明显能力。相比之下，非茎细胞样肿瘤细胞在生存细胞中具有细胞可塑性的营养限制，并具有养分限制的细胞死亡。集体研究，这些研究确定了一种与肿瘤细胞层次结构相关的新型分子机制，该机制可以提供脆弱的节点，因为靶向glut3表达可减少脑肿瘤启动细胞自我更新和肿瘤生长。像所有癌症一样，胶质母细胞瘤显示出沃堡效应，这是对能量供应的有氧糖酵解的首选利用。这种有氧甘油可以使细胞免于氧气需求，并提供合成代谢材料的稳定供应，但高葡萄糖无效，需要稳定的葡萄糖供应，这表明潜在的治疗靶标。基于这种背景，我们假设优先使用葡萄糖来源的碳骨架进行大分子分子生物合成允许脑肿瘤启动细胞在细胞外能量应力下生存，并为这些细胞提供具有不同代谢极限的潜水者的能力。抗血管生成贝伐单抗在肿瘤对治疗的初始反应中表现出了希望，但未能延长生存率。研究表明，血管生成抑制剂耐药性与可能富含肿瘤启动细胞的血管功能和代谢转移有关。为了研究细胞代谢与肿瘤层次结构之间的这些潜在联系，我们将剖析脑肿瘤启动细胞与肿瘤微环境之间的相互作用。在第一个目标中，我们将确定干细胞代谢反应在应激抗性中的作用。在第二个目标中，我们将通过使用人类患者的区域活检和动物研究中特定于区域特定的SIRT 3修饰的区域活检来询问富含肿瘤启动细胞的不同肿瘤微环境中线粒体蛋白的作用。最后，我们将研究通过化学疗法和/或辐射靶向SIRT3的潜在合成致死性。我们将采用一系列源自人胶质母细胞瘤和癫痫组织的模型，为这种致命的脑疾病的高级建模奠定了基础。