Exploiting altered glucose utilization in Bcr-Abl+ Leukemia

描述（由申请方提供）：本提案将尝试描述用于治疗慢性粒细胞白血病（CML）和其他白血病亚群的新型联合治疗。CML由产生Bcr-Abl基因的致癌突变启动并依赖于该突变。用Bcr-Abl酶抑制剂如甲磺酸伊马替尼治疗是目前的标准临床实践。虽然这些抑制剂在慢性期有效控制疾病，但通常不能消除所有CML细胞，也不能实现晚期CML和Bcr-Abl+急性淋巴细胞白血病（ALL）的持久缓解。靶向额外的基因产物与Bcr-Abl抑制剂联合应用对于防止残留的Bcr-Abl+ CML细胞存活和实现持久缓解是必要的。进行无偏倚的大规模遗传筛选以鉴定其抑制作用与甲磺酸伊马替尼治疗协同的基因产物。该筛选确定了几种途径，包括参与细胞能量产生的酶。该提议将检验靶向特定代谢途径将极大地使CML和Bcr-Abl+ ALL细胞对Bcr-Abl抑制敏感的假设。该提案的目标有三个方面：1。确定靶向参与能量产生的酶与IM组合是否协同杀死CML细胞; 2.确定在白血病小鼠模型中靶向这些酶是否减缓疾病进展;和3.以确定靶向这些基因的代谢后果。从临床的角度来看，确定与Bcr-Abl激酶抑制剂协同作用的新靶点可能为临床治疗提供新的选择。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，以克服Bcr-Abl抑制剂的治疗。了解癌症中的葡萄糖利用和能量产生途径对于开发代谢药物疗法至关重要。可以选择性地靶向肿瘤细胞代谢谱改变的药物可能会使细胞对化疗敏感。该提案将帮助国家癌症研究所履行其使命，支持癌症治疗的研究项目，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：慢性髓性白血病细胞表现出改变的能量代谢，使它们能够在当前临床治疗的抑制下存活。该提案将试图描述这些细胞利用的替代能量途径，以设计更好的代谢疗法来靶向这些细胞。

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.)