Exploiting altered glucose utilization in Bcr-Abl+ Leukemia

利用 Bcr-Abl 白血病中葡萄糖利用的改变

基本信息

批准号：
8537126
负责人：
Francesca Alvarez Calderon
金额：
$ 4.22万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2014-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8537126
关键词：
Abbreviations Acute Acute Lymphocytic Leukemia Aldolase C B-Cell Acute Lymphoblastic Leukemia Basic Science Bcr-Abl tyrosine kinase Cancer Etiology Cell Line Cell Proliferation Cell Survival Cells Chromosome 9 Chronic Myeloid Leukemia Chronic Phase Citric Acid Cycle Clinical Clinical Sciences Clinical Treatment Combined Modality Therapy Discipline Disease Progression Disease remission Energy Metabolism Enzymes Exhibits Fatty Acids Fructosediphosphate Aldolase Gene Expression Gene Targeting Generations Genes Genetic Screening Glucose Glyceraldehyde-3-Phosphate Dehydrogenases Goals Imatinib mesylate In Vitro Lactate Dehydrogenase Lead Lentivirus Leukemic Cell Malignant Neoplasms Mass Spectrum Analysis Metabolic Metabolic Pathway Mission Mutation Myeloproliferative disease NMR Spectroscopy National Cancer Institute Pathway interactions Pentosephosphate Pathway Pharmaceutical Preparations Pharmacotherapy Philadelphia Chromosome Philadelphia Chromosome Negative Chronic Myelogenous Leukemia Production Proteins Pyruvate Dehydrogenase Complex RNA Interference Reciprocal Translocation Research Project Grants Residual state Small Interfering RNA System Testing Tissues Training and Education Tricarboxylic Acids Tyrosine Kinase Inhibitor Weight abl Genes cancer therapy chemotherapy clinical practice design dihydrolipoyllysine-residue acetyltransferase disorder control fatty acid oxidation fusion gene genome-wide glucose uptake in vivo inhibitor/antagonist killings kinase inhibitor leukemia long-chain-fatty-acid-CoA ligase loss of function mouse model neoplastic cell novel oxidation prevent public health relevance pyruvate dehydrogenase small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): This proposal will attempt to characterize novel combination therapies for the treatment of chronic myelogenous Leukemia (CML) and other subsets of leukemia. CML is initiated by and dependent on a cancer causing mutation that generates the Bcr-Abl gene. Treatment with inhibitors of the Bcr-Abl enzyme such as Imatinib Mesylate is the current standard clinical practice. While effective in controlling disease in the chronic phase, these inhibitors often fail to eliminate all CML cells and also fail to achieve durable remissions for advanced CML and Bcr-Abl+ acute lymphoblastic leukemias (ALL). Targeting additional gene products in combination with Bcr-Abl inhibitors should be necessary to prevent residual Bcr-Abl+ CML cell survival and achieve durable remissions. An unbiased large-scale genetic screen was performed to identify gene products whose inhibition synergizes with Imatinib Mesylate therapy. This screen identified several pathways including enzymes involved in cellular energy production. This proposal will test the hypothesis that targeting particular metabolic pathways will greatly sensitize CML and Bcr-Abl+ ALL cells to Bcr-Abl inhibition. The goals of this proposal are threefold: 1. To determine whether targeting enzymes involved in energy production in combination with IM cooperates to kill CML cells; 2. To determine whether targeting these enzymes in a mouse model of leukemia slows down disease progression; and 3. To determine what are the metabolic consequences of targeting these genes. From a clinical perspective, identifying novel targets that cooperate with Bcr-Abl kinase inhibitors may provide new alternatives for clinical treatments. From a basic science perspective, it will allow us to dissect important pathways utilized by CML cells to overcome treatment with Bcr-Abl inhibitors. Understanding glucose utilization and energy production pathways in cancers is of critical importance to develop metabolic drug therapies. Drugs that can selectively target the altered metabolic profile of tumor cells may sensitize cells to chemotherapy. This proposal will help the National Cancer Institute fulfill their mission to support research projects for the treatment of cancer and to support education and training in fundamental sciences and clinical disciplines relating to cancer. PUBLIC HEALTH RELEVANCE: Chronic myelogenous leukemia cells exhibit altered energy metabolism that allows them to survive inhibition with current clinical therapy. This proposal will attempt to characterize alternative energy pathways utilized by these cells in an attempt to design better metabolic therapies to target these cells.)

描述（由申请人提供）：该提案将尝试表征用于治疗慢性骨髓性白血病（CML）和其他白血病的新型组合疗法。 CML是由引起产生BCR-ABL基因的突变的癌症引发的，并取决于CML。用BCR-ABL酶（例如伊马替尼甲酸酯）的抑制剂治疗是当前的标准临床实践。尽管在慢性期有效控制疾病，但这些抑制剂通常无法消除所有CML细胞，也无法实现晚期CML和BCR-ABL+急性淋巴细胞性白血病（ALL）的持久缓解。为了防止残留的BCR-ABL+ CML细胞存活并实现持久的缓解，必须将其他基因产物与BCR-ABL抑制剂结合使用。进行了公正的大规模遗传筛选，以鉴定抑制剂与伊马替尼麦甲酸酯治疗协同作用的基因产物。该屏幕确定了几种途径，包括涉及细胞能量产生的酶。该建议将检验以下假设：针对特定代谢途径将极大地敏感CML和BCR-ABL+所有细胞对BCR-ABL抑制作用。该提案的目标是三倍：1。确定是否将涉及能源生产的酶与IM合作者结合使用以杀死CML细胞； 2。确定在白血病小鼠模型中靶向这些酶是否会减慢疾病进展； 3。确定靶向这些基因的代谢后果是什么。从临床角度来看，确定与BCR-ABL激酶抑制剂合作的新型靶标可能为临床治疗提供新的替代方法。从基础科学的角度来看，它将使我们能够剖析CML细胞利用的重要途径来克服用BCR-ABL抑制剂治疗。了解癌症中的葡萄糖利用和能量生产途径对于开发代谢药物疗法至关重要。可以选择靶向肿瘤细胞代谢特征的药物可能会使细胞对化学疗法敏感。该建议将帮助国家癌症研究所履行其支持研究项目的使命，以治疗癌症，并支持与癌症有关的基础科学和临床学科的教育和培训。公共卫生相关性：慢性骨髓性白血病细胞表现出改变的能量代谢，使它们能够通过当前的临床疗法生存抑制。该建议将试图表征这些细胞利用的替代能量途径，以试图设计更好的代谢疗法以靶向这些细胞。