Targeting Microenvironment / Leukemia Cell Interactions in CML

CML 中的靶向微环境/白血病细胞相互作用

基本信息

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
项目类别：
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

项目摘要

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 治疗的最新进展带来了非常高的缓解率，包括血液学缓解率和绝大多数患者的细胞遗传学反应。然而，微小残留病可大多数患者通过 PCR 监测发现。逆转录酶检测Bcr/Abl mRNA水平 PCR 可能低估了残留的白血病负担，因为转录不活跃、静止的 CML 细胞该技术无法检测到。 Bcr/Abl 信号传导负向调节趋化因子的表达 CML 细胞上的受体 CXCR4。 CXCR4 是 SDF-1 的受体，SDF-1 是骨骼产生的主要趋化因子骨髓微环境。 CXCR4 的下调导致 CML 细胞/祖细胞从骨髓进入循环，可能解释 CML 的特征性白细胞增多。我们有最近证明，Bcr/Abl 激酶抑制剂（例如伊马替尼）可上调 CXCR4 表达，并且可能因此有利于 CML 祖细胞在骨髓微环境中的存活。药理抑制特定小分子抑制剂 (AMDSIOO/Plerixafor) 的 CXCR4 在白血病患者中产生了惊人的效果恶性细胞从骨髓释放到循环中以及 CXCR4 介导的抑制白血病细胞中的促生存信号传导，与其动员无关。我们的体外和体内数据骨髓性白血病证明 CXCR4/SDF1 轴的破坏会导致明显的致敏信号转导抑制剂和化疗，从而克服微环境介导的耐药性。一项临床试验正在进行中，并提供了概念验证，即 CXCR4 抑制会导致优先 Ph+白血病细胞的动员。此外，整合素介导白血病细胞在其细胞中的锚定。微环境和 VLA-4 的抑制导致白血病/基质细胞相互作用的破坏，化学增敏。因此我们建议：具体目标 1. 检验抑制 CXCR4 和/或 VLA-4 会导致 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。具体目标 2. 检验 Nutlin-3a 在慢性期非基因毒性激活 p53 的假设，以及急变期 CML 通过抑制 SDF-1/CXCR4 破坏白血病/基质相互作用。具体目标 3. 研究酪氨酸激酶和 Bcl-2 联合抑制对小鼠存活的潜力体外和体内骨髓微环境中的静态 CML 祖细胞。我们期望这些研究能够提高我们对 CML 细胞及其之间复杂相互作用的理解。微环境并为消除残留的 CML 祖细胞提供基于机制的原理。