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: 8794425
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794425
• 关键词: Accounting; Bone Marrow; Cell Proliferation; Cell Survival; Cells; Clinical; Complex; Dasatinib; Development; Disease remission; Elements; Event; Exhibits; FDA approved; Feedback; Future; Generations; Genetic Translation; Healthcare; Laboratories; Lead; Leukemic Cell; Malignant Neoplasms; Mediating; Metabolic; Molecular; Morbidity - disease rate; Mus; Mutation; Natural History; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Ph+ ALL; Play; Process; Property; Protein Biosynthesis; Proteins; Refractory; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Sirolimus; Stem cells; Stream; Tyrosine Kinase Inhibitor; Veterans; Work; antileukemic agent; base; bcr-abl Fusion Proteins; cell transformation; cellular targeting; design; human FRAP1 protein; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; leukemogenesis; mTOR Inhibitor; mTOR inhibition; mortality; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; patient population; progenitor; public health relevance; reconstitution; response; sensor; therapeutic target; translational approach

DESCRIPTION (provided by applicant): Targeting BCR-ABL with specific kinase inhibitors has resulted in remarkable clinical advances and has dramatically changed the outcome of patients with CML and Ph+ ALL. Despite that, the emergence of leukemic cell resistance raises serious concerns and the need for the development of approaches to overcome this resistance. It is also important to note that there is now evidence that, TKIs do not eliminate leukemia initiating stem cells (LICs), even in sensitive cases where complete remission is achieved. Thus, efforts to target cellular pathways down-stream of BCR-ABL, circumventing resistance at the BCR-ABL level, may provide an important clinical approach for the treatment of such Ph+ leukemias and the elimination of LICs. Work from our laboratory has established that the mTOR pathway is deregulated in Ph+ leukemias and has raised the possibility that such deregulation contributes to the emergence of leukemic cell resistance. We have provided evidence on the existence of two functionally distinct mTORC1 complexes in BCR-ABL transformed cells, rapamycin-sensitive (RS) and rapamycin-insensitive (RI) mTORC1, and shown that RI-mTORC1 plays critical roles in the regulation of mRNA translation for oncogenic proteins that promote leukemic cell proliferation. We have also established that mTORC2 complexes are formed and their activation is important for survival of leukemia cells and primary Ph+ leukemic precursors. Using a unique dual catalytic inhibitor of mTORC1 and mTORC2, OSI-027, we have established that targeting such complexes results in potent suppressive effects on primitive leukemic precursors from CML patients and cells expressing the T315I BCR- ABL mutation. In parallel efforts to target the AMPK metabolic-sensor pathway in Ph+ cells, we found that AMPK inducers suppress RI-mTORC1 complexes, resulting in potent antileukemic effects. Such agents also overcome resistance in cells expressing refractory BCR-ABL mutations, such as T315I. These findings raise the prospect of future translational approaches to overcome resistance in CML and Ph+ ALL by directly targeting RI-mTORC1 and mTORC2 complexes and/or by engaging AMPK. The current proposal is a systematic approach to define the mechanisms of deregulation of mTOR pathways in Ph+ leukemias and to identify downstream effectors that could be therapeutically targeted. In addition it involves studies to identify feedback pathways that account for leukemic cell resistance and to use agents that target such pathways to eliminate LICs in Ph+ leukemias. Specific aim 1 will dissect BCR-ABL-regulated signaling events that control mTORC2 and RI-mTORC1 complexes and will define the regulatory effects of AMPK modulation in the process. Specific aim 2 will identify downstream effectors of mTORC1 and mTORC2 complexes and will systematically define the relevance of targeting distinct effectors in the generation of antileukemic responses. Specific aim 3 will employ CML mouse models for TKI sensitive and resistant (T315I- BCR-ABL) CML to examine the in vivo antileukemic properties of mTORC1/2 targeting agents. Finally, specific aim 4 will systematically study the effects of OSI-027 and AMPK activators on primary cells from a large number of patients with CML and Ph+ ALL and their effects on survival of leukemia initiating stem cells (LICs). It will also examine the activaion of negative feedback pathways and will define the effects of combinations of dual mTORC2/mTORC1 agents with different modulators of feedback loops, to promote elimination of LICs. Altogether, these studies should advance our understanding of the mechanisms of BCR-ABL-mediated leukemogenesis and provide the rationale for future clinical-translational efforts involving the use of dual mTORC1/2 catalytic inhibitors and/or AMPK activators for the treatment of resistant CML and Ph+ ALL.

描述（由申请人提供）： 使用特定激酶抑制剂靶向 BCR-ABL 已取得显着的临床进展，并极大地改变了 CML 和 Ph+ ALL 患者的预后。尽管如此，白血病细胞耐药性的出现引起了人们的严重关注，并且需要开发克服这种耐药性的方法。还需要注意的是，现在有证据表明，即使在实现完全缓解的敏感病例中，TKIs 也不能消除白血病起始干细胞 (LIC)。因此，针对 BCR-ABL 下游细胞通路的努力，规避 BCR-ABL 水平的耐药性，可能为治疗此类 Ph+ 白血病和消除 LIC 提供重要的临床方法。我们实验室的工作已经确定，mTOR 通路在 Ph+ 白血病中失调，并提出了这种失调导致白血病细胞耐药性出现的可能性。我们提供了证据证明 BCR-ABL 转化细胞中存在两种功能不同的 mTORC1 复合物，即雷帕霉素敏感 (RS) 和雷帕霉素不敏感 (RI) mTORC1，并表明 RI-mTORC1 在调节促进白血病细胞增殖的致癌蛋白 mRNA 翻译中发挥着关键作用。我们还确定 mTORC2 复合物的形成及其激活对于白血病细胞和原发性 Ph+ 白血病前体细胞的存活很重要。使用一种独特的 mTORC1 和 mTORC2 双催化抑制剂 OSI-027，我们已经确定，靶向此类复合物会对来自 CML 患者的原始白血病前体和表达 T315I BCR-ABL 突变的细胞产生有效的抑制作用。在针对 Ph+ 细胞中 AMPK 代谢传感器途径的平行努力中，我们发现 AMPK 诱导剂抑制 RI-mTORC1 复合物，从而产生有效的抗白血病作用。此类药物还克服了表达难治性 BCR-ABL 突变（例如 T315I）的细胞的耐药性。这些发现提出了未来通过直接靶向 RI-mTORC1 和 mTORC2 复合物和/或通过参与 AMPK 来克服 CML 和 Ph+ ALL 耐药性的转化方法的前景。目前的提议是一种系统方法，用于定义 Ph+ 白血病中 mTOR 通路失调的机制，并确定可以作为治疗目标的下游效应器。此外，它还涉及研究以确定导致白血病细胞耐药的反馈途径，并使用针对此类途径的药物来消除 Ph+ 白血病中的 LIC。具体目标 1 将剖析控制 mTORC2 和 RI-mTORC1 复合物的 BCR-ABL 调节的信号传导事件，并定义该过程中 AMPK 调节的调节作用。具体目标 2 将确定 mTORC1 和 mTORC2 复合物的下游效应器，并将系统地定义针对不同效应器在产生抗白血病反应中的相关性。具体目标 3 将采用 TKI 敏感和耐药 (T315I-BCR-ABL) CML 的 CML 小鼠模型来检查 mTORC1/2 靶向药物的体内抗白血病特性。最后，具体目标4将系统地研究OSI-027和AMPK激活剂对大量CML和Ph+ ALL患者的原代细胞的影响及其对白血病起始干细胞（LIC）存活的影响。它还将检查负反馈途径的激活，并定义双 mTORC2/mTORC1 药物与不同反馈环调节剂的组合的效果，以促进 LIC 的消除。总而言之，这些研究应增进我们对 BCR-ABL 介导的白血病发生机制的理解，并为未来涉及使用双重 mTORC1/2 催化抑制剂和/或 AMPK 激活剂治疗耐药 CML 和 Ph+ ALL 的临床转化工作提供理论基础。