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（由申请人提供）：人类大脑是代谢最活跃的器官之一，具有高效提取葡萄糖作为能量和碳源主要货币的能力。通过表达高亲和力葡萄糖转运蛋白优先从营养受限的环境中吸收葡萄糖最常见的原发性脑肿瘤，胶质母细胞瘤，是最致命的人类癌症之一，与正常大脑一样，胶质母细胞瘤也包含具有自我更新能力的细胞层次结构。这些脑肿瘤起始细胞位于顶端。表现出治疗抗性，促进肿瘤血管生成，并侵入正常组织，为模拟其调节和制定靶向策略提供了理论依据。我们最近证明，脑肿瘤起始细胞通过共同选择表现出显着的生存能力，能够在肿瘤性脑中发现的营养水平降低的情况下生存。相比之下，非干细胞样肿瘤细胞在营养限制的情况下发生细胞死亡，并且存活细胞具有向干细胞样状态的细胞可塑性。与肿瘤细胞层次结构相关的分子机制，可以提供一个脆弱节点，因为靶向 GLUT3 表达会减少脑肿瘤启动细胞的自我更新和肿瘤生长，与所有癌症一样，胶质母细胞瘤表现出瓦伯格效应，即优先利用有氧糖酵解来提供能量。这种有氧糖酵解使细胞摆脱对氧气的需求，并提供稳定的合成代谢物质供应，但葡萄糖效率很高，需要稳定的葡萄糖供应，这表明了一种潜在的治疗方法。基于这一背景，我们努力优先使用葡萄糖衍生的碳主链进行大分子生物合成，使脑肿瘤起始细胞能够在细胞外能量应激下生存，并为这些细胞提供占据具有不同代谢限制的多种生态位的能力。抗血管生成贝伐单抗在肿瘤对治疗的初始反应中显示出希望，但未能延长生存期。研究表明，血管生成抑制剂耐药性与血管功能受损和可能丰富肿瘤的代谢变化有关。为了研究细胞代谢与肿瘤层级之间的潜在联系，我们将剖析脑肿瘤起始细胞与肿瘤微环境之间的相互作用。第一个目标是确定干细胞代谢反应在应激抵抗中的作用。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的区域特异性 SIRT3 修饰，探讨线粒体蛋白翻译后修饰在富含肿瘤起始细胞的不同肿瘤微环境中的作用。最后，我们将研究化疗和/或放疗靶向 SIRT3 的潜在综合致死率。我们将采用一系列源自人类胶质母细胞瘤和癫痫组织的模型，为这种致命性脑疾病的高级建模奠定基础。