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: 8680021
• 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/8680021
• 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; 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）： 用特定的激酶抑制剂靶向BCR-ABL已导致显着的临床进展，并大大改变了CML和PH+患者的结果。尽管如此，白血病细胞抗性的出现仍引起了严重的关注，并需要开发克服这种抵抗力的方法。同样重要的是要注意，现在有证据表明，即使在实现完全缓解的敏感情况下，TKI也不会消除启动干细胞（LIC）的白血病。因此，靶向BCR-ABL下方的细胞途径，在BCR-ABL水平上规避抗性的努力可能为治疗这种pH+白血病的治疗和消除LIC提供重要的临床方法。我们实验室的工作已经确定，MTOR途径在pH+白血病中受到放大管制，并增加了这种放松管制有助于白血病细胞耐药性出现的可能性。我们提供了有关BCR-ABL转化细胞中两个功能上不同的MTORC1复合物，雷帕霉素敏感（RS）和雷帕霉素不敏感（RI）MTORC1中存在的证据，并表明RI-MTORC1在调节MRNA转移的肿瘤蛋白中的MRNA转移中扮演着关键的作用。我们还确定形成了MTORC2复合物，它们的激活对于白血病细胞和原发性pH+白血病前体的存活至关重要。使用MTORC1和MTORC2的独特双催化抑制剂，OSI-027，我们确定靶向这种复合物会导致对CML患者的原始白血病前体和表达T315I BCR-ABL突变的细胞的有效抑制作用。在靶向pH+细胞中AMPK代谢传感器途径的同时努力中，我们发现AMPK诱导剂抑制了Ri-MTORC1复合物，从而导致有效的抗血清效应。这些药物还克服了表达难治性BCR-ABL突变（例如T315i）的细胞中的耐药性。这些发现通过直接靶向RI-MTORC1和MTORC2复合物和/或通过吸引AMPK来克服CML和PH+的抗药性的未来转化方法的前景。当前的建议是一种系统的方法，用于定义pH+白血病中MTOR途径放松管制的机制，并识别可以针对治疗靶向的下游效应子。此外，它涉及研究以识别解释白血病细胞耐药性的反馈途径，并使用针对此类途径的药物来消除pH+白血病中的lics。具体的目标1将剖析控制MTORC2和RI-MTORC1复合物的BCR-ABL调节的信号事件，并将定义AMPK调制在此过程中的调节作用。特定的目标2将识别MTORC1和MTORC2复合物的下游效应子，并系统地定义靶向抗肺反应产生不同效应子的相关性。特定的目标3将采用CML小鼠模型来进行TKI敏感和抗性（T315i-BCR-ABL）CML，以检查MTORC1/2靶向剂的体内抗肺部特性。最后，特定的目标4将系统地研究来自大量CML和PH+患者的OSI-027和AMPK激活剂对启动干细胞（LICS）的白血病生存的影响的主要细胞的影响。它还将检查负反馈途径的激活，并将定义具有不同反馈回路调节剂的双MTORC2/MTORC1代理的组合，以促进消除LIC。总而言之，这些研究应提高我们对BCR-ABL介导的白血病的机制的理解，并为未来的临床翻译工作提供了理由，涉及使用双MTORC1/2催化抑制剂和/或AMPK激活剂来治疗耐药性CML和PH++ All。