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.

这是一个竞争性的更新应用，专注于白血病发生的机制和 急性髓系白血病(AML)治疗新靶点的确定开发新的治疗方法 作为结果，急性髓细胞白血病的治疗方法具有很高的临床翻译相关性和重要性 对于大多数急性髓系白血病(AML)患者来说，尽管最近在治疗方面取得了进展，但仍非常糟糕 田野。白血病细胞耐药的出现仍然是一个严重的问题，并确认 靶向消除白血病干细胞(LSCs)的途径将具有很高的相关性和 重要性。我们实验室的研究为负反馈调控的存在提供了证据 髓系白血病细胞中参与化疗或其他抗肿瘤药物反应的环路 并介导白血病细胞耐药。其中包括丝裂原活化蛋白激酶(MAPK)的激活。 级联和其他监管负反馈循环。 MNK1和MNK2是MAPK通路的关键效应者，控制着MAPK的磷酸化。 真核细胞起始因子4E(EIF4E)是帽-翻译起始复合体的关键元件，其功能 对肿瘤细胞的恶性转化和生存至关重要。此外，我们小组的工作已经 如果首次有证据表明MNK激酶以负反馈调节方式激活， 介导eIF4E磷酸化，促进急性髓系白血病原始白血病前体细胞存活。因为 在eIF4E在肿瘤发生中的关键作用中，使用MNK激酶抑制剂靶向这一信号级联可能 提供一种独特的方法来瞄准和消除LSC。目前的提案是一种系统性的方法，以 明确MNK激酶促进急性髓系白血病患者LSC存活的机制，并旨在利用这些信息 寻找新的细胞成分以选择性靶向LSCs并开发新的治疗方法 对于急性髓系白血病。特异性目标1将定义急性髓系白血病祖细胞中的MNK效应通路，并将剖析其 在白血病发生中的作用。将进行实验以确定MNK调节的效应器的作用 控制致癌基因的转录、加工、细胞增殖和白血病前体细胞的存活。 此外，MNK1和MNK2在白血病发生中的不同要求及其调节作用 在下游的小路上将被解剖。具体目标2将研究MNK激酶和MNK的作用 AML模型体内抗白血病反应中的效应通路。将建立急性髓系白血病小鼠模型 单个Mnk1-/-、Mnk2-/-或双Mnk1-/-2-/-基因敲除小鼠，以及不同MNK激酶对小鼠脑内MNK的影响 白血病的发生和对化疗和其他反应的抗白血病反应的产生 将涉及抗白血病药物。类似的研究将使用突变的eif4E敲入小鼠进行，在 其中eIF4E不能进行MNK介导的磷酸化。特定目标3检测抗白血病药物 新型MNK抑制剂对AML患者原发白血病前体细胞和LSCs的作用 尝试以负面反馈循环为目标，以增强反应。新型MNK抑制剂对血管紧张素转换酶的影响 将检测大量AML患者的原代细胞及其对LSCs存活的影响 将会被定义。负反馈通路的激活也将被评估，以及 MNK抑制剂与mTOR靶向剂或此类反馈环的其他调节剂的组合 白血病干细胞存活将被定义。 总之，这些研究应该会促进我们对白血病发生机制的理解和 为未来重要的临床转化工作提供基础，包括使用新的靶向抑制剂 MNK激酶或其效应器治疗急性髓系白血病。