Exploiting altered glucose utilization in Bcr-Abl+ Leukemia

描述(由申请人提供)：这项提案将尝试描述治疗慢性粒细胞白血病(CML)和其他白血病亚型的新的联合疗法。慢性粒细胞白血病是由一种产生bcr-abl基因的致癌突变引发的，并依赖于这种突变。使用bcr-abl酶的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，但往往无法消除所有CML细胞，也无法实现对晚期CML和BCR-Abl+急性淋巴细胞白血病(ALL)的持久缓解。靶向更多的基因产物与bcr-abl抑制剂结合应该是必要的，以防止残留的bcr-abl+CML细胞存活并实现持久的缓解。进行了一项无偏见的大规模遗传筛选，以确定其抑制作用与甲磺酸伊马替尼治疗协同的基因产物。这一筛选确定了几种途径，包括参与细胞能量产生的酶。这项提议将检验这样一个假设，即靶向特定的代谢途径将使CML和BCR-Abl+ALL细胞对BCR-Abl抑制非常敏感。这项提议的目标有三个：1.确定靶向参与能量产生的酶与IM结合是否能协同杀死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；3.确定靶向这些基因的代谢后果是什么。从临床角度来看，识别与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慢性粒细胞白血病细胞用来克服bcr-abl抑制剂治疗的重要途径。了解癌症中葡萄糖的利用和能量产生途径对于开发代谢药物疗法至关重要。可以选择性地针对改变的肿瘤细胞代谢特征的药物可能会使细胞对化疗敏感。这项提议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，并支持与癌症相关的基础科学和临床学科的教育和培训。 公共卫生相关性：慢性髓细胞白血病细胞表现出能量代谢的改变，使它们能够在目前的临床治疗中幸存下来。这项提议将试图描述这些细胞利用的替代能量途径，试图设计更好的新陈代谢疗法来针对这些细胞。)

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.)