Signaling Pathways and Therapeutic Targeting of Leukemic Cells

白血病细胞的信号通路和治疗靶向

• 批准号: 10292420
• 负责人: LEONIDAS C. PLATANIAS
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292420
• 关键词: Acute Myelocytic Leukemia; Address; Aging; Antineoplastic Agents; Area; Automobile Driving; Cell Proliferation; Cells; Clinical; Complex; Development; Disease; Dysmyelopoietic Syndromes; Elements; Eukaryotic Initiation Factor-4E; FMRP; FRAP1 gene; Feedback; Future; Generations; Genetic Translation; Growth Factor Receptors; High Prevalence; Knock-in Mouse; Knockout Mice; Laboratories; Leukemic Cell; Malignant - descriptor; Mediating; Mitogen-Activated Protein Kinases; Morbidity - disease rate; Myeloproliferative disease; New Agents; Normal Cell; Oncogenic; Outcome; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Population; Property; Proteins; Receptor Signaling; Refractory; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Therapeutic Agents; Toxic effect; Translation Initiation; Work; acute myeloid leukemia cell; antileukemic agent; cancer stem cell; chemotherapy; experimental study; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; leukemia; leukemic stem cell; leukemogenesis; mortality; mouse model; mutant; myeloid leukemia cell; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; older patient; precision medicine; precursor cell; progenitor; response; stem cell survival; targeted agent; therapeutic target; tumorigenesis

This is a competing renewal application focused on the mechanisms of leukemogenesis and the identification of new targets for the treatment of acute myeloid leukemia (AML). Developing novel therapeutic approaches for the treatment of AML is of high clinical translational relevance and importance, as the outcome for the majority of patients with acute myeloid leukemia (AML) remains very poor, despite recent advances in the field. The emergence of leukemic cell resistance continues to be a serious problem and identifying pathways that can be targeted to eliminate leukemia stem cells (LSCs) would be of high relevance and importance. Work from our laboratory has provided evidence for the existence of negative feedback regulatory loops in myeloid leukemia cells that are engaged in response to chemotherapy or other antineoplastic agents and mediate leukemic cell resistance. These include activation of mitogen activated protein kinase (MAPK) cascades and other regulatory negative feedback loops. The kinases MNK1 and MNK2 are key effectors of MAPK pathways and control phosphorylation of the eukaryotic initiation factor 4E (eIF4E), a key element of the cap-translation initiation complex, whose function is critical for malignant transformation and survival of neoplastic cells. In addition, work from our group has provided the first evidence that MNK kinases are activated in a negative feedback regulatory manner to mediate eIF4E phosphorylation and to promote survival of primitive leukemic precursor cells in AML. Because of such key roles for eIF4E in tumorigenesis, targeting this signaling cascade using MNK kinase inhibitors may provide a unique approach to target and eliminate LSCs. The current proposal is a systematic approach to define the mechanisms by which MNK kinases promote LSC survival in AML and aims to use such information towards identifying novel cellular elements to selectively target LSCs and develop new therapeutic approaches for AML. Specific aim 1 will define MNK effector pathways in AML leukemic progenitors and will dissect their contributions in leukemogenesis. Experiments will be performed to define the roles of MNK-regulated effectors in controlling oncogenic mRNA translation, processing, cell proliferation, and survival of leukemic precursors. In addition the differential requirement of MNK1 versus MNK2 in leukemogenesis and their regulatory effects on downstream pathways will be dissected. Specific Aim 2 will examine the roles of MNK kinases and effector pathways in antileukemic responses in AML models in vivo. AML mouse models will be established in single Mnk1-/- or Mnk2-/- or double Mnk1-/-2-/- knockout mice, and the impact of different MNK kinases in leukemogenesis and generation of antileukemic responses in response to chemotherapy and other antileukemic agents will be addressed. Similar studies will be performed using mutant eIF4E knock-in mice, in which eIF4E cannot undergo MNK-mediated phosphorylation. Specific aim 3 examine the antileukemic properties of novel MNK inhibitors on primary leukemic precursors and LSCs from AML patients and will attempt to target negative feedback loops to enhance responses. The effects of novel MNK inhibitors on primary cells from a large number of patients with AML will be examined and their effects on survival of LSCs will be defined. The activation of negative feedback pathways will be also assessed and the effects of combinations of MNK inhibitors with mTOR targeting agents or other modulators of such feedback loops on leukemic stem cell survival will be defined. Altogether, these studies should advance our understanding of the mechanisms of leukemogenesis and provide the basis for important future clinical-translational efforts involving the use of novel inhibitors targeting MNK kinases or their effectors for the treatment of AML.

这是一个竞争性更新应用，重点介绍了白血病的机制和 确定治疗急性髓样白血病（AML）的新靶标。发展新颖的治疗性 作为结果，AML治疗AML的方法具有很高的临床翻译相关性和重要性 对于大多数急性髓性白血病（AML）的患者，尽管最近进展进展，但仍很差 领域。白血病细胞耐药性的出现仍然是一个严重的问题，并确定 可以针对消除白血病干细胞（LSC）的途径具有很高的相关性，并且 重要性。我们实验室的工作为存在负面反馈调节提供了证据 响应化学疗法或其他抗肿瘤剂的髓样白血病细胞中的环。 并介导白血病细胞耐药性。这些包括激活有丝分裂原活化蛋白激酶（MAPK） 级联和其他监管负反馈循环。 激酶MNK1和MNK2是MAPK途径的关键效应因子，并控制了磷酸化的磷酸化 真核生物起始因子4E（EIF4E），这是盖式翻译起始复合物的关键要素，其功能 对于肿瘤细胞的恶性转化和存活至关重要。此外，我们小组的工作有 提供第一个证据表明MNK激酶以负反馈调节方式激活到 介导EIF4E磷酸化并促进AML中原始白血病前体细胞的存活。因为 EIF4E在肿瘤发生中的关键作用，使用MNK激酶抑制剂靶向该信号级联 提供一种独特的方法来靶向和消除LSC。当前的建议是一种系统的方法 定义MNK激酶在AML中促进LSC生存的机制，并旨在使用此类信息 识别新型的细胞元素，以选择性地靶向LSC并开发新的治疗方法 对于AML。特定的目标1将定义AML白血病祖细胞中的MNK效应途径，并将剖析其 白血病的贡献。将进行实验以定义MNK调节效应子的作用 在控制致癌的mRNA翻译，加工，细胞增殖和白血病前体的存活中。 此外 将在下游通路上进行解剖。具体目标2将检查MNK激酶的作用和 AML模型中抗白血病反应的效应途径。 AML鼠标模型将在 单个MNK1 - / - 或MNK2 - / - 或Double Mnk1 - / - 2 - / - 敲除小鼠，以及不同MNK激酶在 响应化学疗法和其他的白血病生成和抗白血病反应的产生 将解决抗血清药物。将使用突变的EIF4E敲入小鼠进行类似的研究 EIF4E不能经历MNK介导的磷酸化。特定目的3检查抗血流 新型MNK抑制剂对AML患者原发性白血病前体和LSC的特性，将 尝试针对负面反馈循环以增强响应。新型MNK抑制剂对 将检查来自大量AML患者的主要细胞，并将其对LSC存活的影响 将定义。还将评估负反馈途径的激活以及 MNK抑制剂与MTOR靶向剂或此类反馈循环的其他调节剂的组合 将定义白血病干细胞存活。 总之，这些研究应提高我们对白血病机制和 为未来重要的临床翻译工作提供了基础，涉及使用新型抑制剂靶向 MNK激酶或其治​​疗AML的效应子。