Targeting Microenvironment / Leukemia Cell Interactions in CML

CML 中的靶向微环境/白血病细胞相互作用

• 批准号: 8000073
• 负责人: MICHAEL ANDREEFF
• 金额: $ 19.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000073
• 关键词: Apoptosis; Apoptotic; Blast Phase; Blood Circulation; Bone Marrow; CD34 gene; CXCR; CXCR4 Receptors; CXCR4 gene; Cell Communication; Cell Death; Cells; Characteristics; Chemosensitization; Chronic Myeloid Leukemia; Chronic Phase; Clinical Trials; Complex; Cytogenetics; Data; Disabled Persons; Disease remission; Down-Regulation; Employee Strikes; Gleevec; Imatinib; In Vitro; Integrin alpha4beta1; Integrins; Leukemic Cell; Leukocytosis; Lymphoblastic Leukemia; Lymphoid; Mediating; Messenger RNA; Monitor; Mutation; Myelogenous; Myeloid Leukemia; Patients; Pharmaceutical Preparations; Phosphotransferases; Protein Family; Protein Tyrosine Kinase; Relapse; Reporting; Research Proposals; Residual Neoplasm; Residual state; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Stem cells; TP53 gene; Techniques; Testing; Therapeutic; Tyrosine Kinase Inhibitor; Up-Regulation; base; cancer cell; chemokine; chemokine receptor; chemotherapy; improved; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; mimetics; novel; overexpression; progenitor; response; small molecule

Recent advances in the therapy of CML have resulted in a very high remission rate, including hematologic and cytogenetic responses in the vast majority of patients. However, minimal residual disease can be detected in most patients by PCR monitoring. Levels of Bcr/Abl mRNA detected by reverse transcriptase PCR probably underestimate the residual leukemia burden, as transcriptionally inactive, quiescent CML cells cannot be detected by this technique. Bcr/Abl signaling negatively regulates the expression ofthe chemokine receptor CXCR4 on CML cells. CXCR4 is the receptor for SDF-1, a major chemokine produced by the bone marrow microenvironment. Downregulation of CXCR4 results in release of CML cells/progenitor cells from the bone marrow into the circulation and may explain the characteristic leucocytosis of CML. We have recently demonstrated that Bcr/Abl kinase inhibitors such as imatinib upregulate CXCR4 expression and may therefore favor the survival of CML progenitor cells in the bone marrow niche. Pharmacological inhibition of CXCR4 by a specific small molecule inhibitor (AMDSIOO/Plerixafor) in leukemia patients resulted in striking release of malignant cells from the bone marrow into the circulation and in the CXCR4-mediated inhibition of pro-survival signaling in the leukemic cells, independent of their mobilization. Our in vitro and in vivo data in myeloid leukemias demonstrated that disruption ofthe CXCR4/SDF1 axis results in pronounced sensitization to signal transduction inhibitors and chemotherapy thus overcoming microenvironment-mediated resistance. A clinical trial is ongoing and has provided proof-of-concept, i.e. that CXCR4 inhibition results in preferential mobilization of Ph+ leukemia cells. In addition, integrins mediate anchoring of leukemic cells in their microenvironment and inhibition of VLA-4 resulted in disruption of leukemia/stroma cell interactions and chemosensitization. We therefore propose: Specific Aim 1. To test the hypothesis that inhibition of CXCR4 and/or VLA-4 results in disruption of CML/stroma interactions and thus reverses microenvironment-mediated protection of CML progenitor cells to tyrosine kinase inhibitors. Specific Aim 2. To test the hypothesis that non-genotoxic activation of p53 by Nutlin-3a in chronic phase and blast crisis CML disrupts leukemia/stroma interactions via SDF-1/CXCR4 inhibition. Specific Aim 3. To investigate the potential of combined tyrosine kinase and Bcl-2 inhibition on the survival of quiescent CML progenitor cells in the bone marrow microenvironment in vitro and in vivo. We expect these studies to improve our understanding of the complex interactions between CML cells and their microenvironment and provide mechanism-based rationale for eliminating residual CML progenitor cells.

CML治疗的最新进展导致了非常高的缓解率，包括血液学 以及绝大多数患者的细胞遗传学反应。然而，最小的残留疾病可以是 通过聚合酶链式反应监测在大多数患者中检测到。逆转录酶检测bcr/abl基因表达水平 聚合酶链式反应可能低估了残留的白血病负担，因为它是转录不活跃、静止的CML细胞 不能被这种技术检测到。Bcr/Abl信号负性调节趋化因子的表达 CML细胞上的CXCR4受体。CXCR4是SDF-1的受体，SDF-1是骨骼产生的一种主要趋化因子 骨髓微环境。CXCR4下调导致CML细胞/祖细胞从 骨髓进入循环，可以解释慢性粒细胞白血病的特征白细胞增多症。我们有 最近证明，bcr/abl激酶抑制剂如伊马替尼上调CXCR4的表达，并可能 因此有利于CML祖细胞在骨髓中的存活。药理抑制作用 白血病患者应用一种特异性小分子抑制剂(AMDSIOO/Plerixafor)治疗CXCR4的结果显著 恶性细胞从骨髓释放到循环中，并在CXCR4介导的抑制 白血病细胞中的支持生存信号，不依赖于它们的动员。我们的体外和体内数据 髓系白血病表明，CXCR4/SDF1轴的破坏会导致明显的敏化 信号转导抑制剂和化疗，从而克服微环境介导的耐药性。 一项正在进行的临床试验已经提供了概念验证，即CXCR4抑制导致优先 动员Ph+白血病细胞。此外，整合素介导白血病细胞在其体内的锚定 微环境和VLA-4的抑制导致白血病/基质细胞相互作用的中断 化学增敏。因此，我们建议： 具体目的1.检验抑制CXCR4和/或VLA-4导致细胞外信号转导中断的假设 CML/基质相互作用，从而逆转微环境介导的CML祖细胞保护 酪氨酸激酶抑制剂。 具体目的2.检验慢性期和慢性期Nutlin-3a对P53的非遗传毒性激活假设 急变期CML通过抑制SDF-1/CXCR4来干扰白血病/间质的相互作用。 具体目的3.探讨酪氨酸激酶和Bcl2联合抑制对人卵巢癌细胞存活的影响 体内和体外骨髓微环境中静止的CML祖细胞。 我们希望这些研究能提高我们对慢性粒细胞白血病细胞和细胞之间复杂相互作用的理解。 为消除残留的CML祖细胞提供了基于机制的理论基础。