Combined inhibition of CXCR4 and FLT3-ITD signaling in acute myeloid leukemia

联合抑制急性髓系白血病中的 CXCR4 和 FLT3-ITD 信号传导

• 批准号: 7897533
• 负责人: MICHAEL ANDREEFF
• 金额: $ 33.64万
• 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: 2010-04-05 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897533
• 关键词: AMD3100; Acute Myelocytic Leukemia; Animal Model; Antineoplastic Agents; Apoptosis; Apoptotic; Ara-C; BAY 54-9085; Biological; Blast Cell; Blood Cells; Blood Circulation; Bone Marrow; CSF3 gene; CXCR4 Receptors; CXCR4 gene; Cell Count; Cell Cycle; Cell Death; Cell Survival; Cells; Cleaved cell; Clinical; Clinical Data; Clinical Trials; Code; Coupled; Cytotoxic Chemotherapy; Data; Development; Disease; Disease remission; Dose; Drug Delivery Systems; FDA approved; Genes; Genotype; Hematopoietic; Hematopoietic Stem Cell Mobilization; Homing; In complete remission; Integrins; Leukemic Cell; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Marrow; Mediating; Mutation; Normal Cell; Outcome; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Play; Refractory; Regimen; Relapse; Reporting; Residual Neoplasm; Resistance; Role; Safety; Signal Transduction; Staging; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Testing; Therapeutic; Time; Toxic effect; Treatment Failure; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factor Receptor-1; analog; base; cell stroma; chemokine receptor; chemotherapy; clinical efficacy; design; improved; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; leukemia; mutant; outcome forecast; phase 1 study; public health relevance; response; stem

DESCRIPTION (provided by applicant): The prognosis of patients with relapsed acute myeloid leukemia (AML) harboring FLT3 mutations is extremely poor. We have demonstrated that microenvironment/leukemia interactions play a major role in the chemoresistance of leukemic stem cells and that the SDF-1a/CXCR4 axis is a key regulator of this interaction. We recently discovered that Sorafenib is a superb FLT3-ITD inhibitor with high clinical single agent activity, including complete remissions in Phase I studies 1,2. High CXCR4 levels are associated with poor prognosis4, and FLT3 mutations upregulate CXCR45. We recently reported that inhibition of CXCR4 with an analogue of the FDA approved CXCR4 inhibitor AMD3100( Plerixafar) resulted in mobilization of leukemic cells and sensitization to the pro-apoptotic effects of Sorafenib6. G- CSF cleaves SDF-1, down-regulates CXCR4, was found to be highly synergistic with AMD3100 in mobilization hematopoietic stem cells9 and was recently approved by FDA. We have reported that AML patients in remission, who were treated with AMD3100/G-CSF, had massive egress of AML cells into the circulation, providing first proof of principle for leukemia cell mobilization10. In addition, we observed preferential mobilization of AML over normal cells, both in AML patients in CR and in patients with active disease who received AMD3100/G-CSF as part of a preparative regimen followed by SCT, further supporting the validity of this therapeutic concept. Of note, Sorafenib has no toxicity against normal hematopoietic cells. Based on these findings, we propose to test the hypothesis that mobilization of leukemic stem cells by disruption of SDF-1a/CXCR4 by AMD3100/G-CSF results in improved anti-leukemia activity of Sorafenib in AML patients with mutant FLT3. In addition, we will study the effects of this targeted therapy on non-mobilized AML blasts. We will conduct a clinical trial to determine the safety and efficacy of AMD3100, G-CSF and escalating doses of the FLT3-ITD inhibitor Sorafenib in patients with AML harboring FLT3-ITD mutations and study the in vivo biological effects of disrupting SDF-1a/CXCR4 interactions by AMD3100/G-CSF. Patients with FLT3-ITD mutations can have variable numbers of cells with three distinct FLT3 genotypes : heterozygous FLT3-ITD, homozygous FLT3-ITD and wild type FLT3. Therefore, we will also determine, by single-cell PCR, the effects of this therapy against cells carrying these genotypes, during mobilization with AMD3100/G-CSF and following treatment with sorafenib. Taken together, these studies will establish the safety and anti-leukemia activity of AMD3100/G- CSF/sorafenib and provide a comprehensive assessment of mechanisms involved in leukemia cell mobilization and inhibition of cell signaling. PUBLIC HEALTH RELEVANCE: Acute myelogenous leukemia is a mostly fatal disease, in particular in patients whose leukemia cells are characterized by a mutation in the FLT3 gene. We have recently found, that the drug Sorafenib, which is FDA approved for certain other cancers, is a superb inhibitor of cells carrying this mutation, resulting in complete clearance of leukemia cells from the blood and a reduction in bone marrow leukemia cells. We are proposing to combine sorafenib with a blocker of the chemokine receptor CXCR4, AMD3100(Plerixafor), in a clinical trial in relapsed/refractory patients with AML carrying the FLT3-ITD mutation with the aim of determining the safety and efficacy of this approach.

描述（由申请人提供）：携带FLT 3突变的复发性急性髓性白血病（AML）患者的预后极差。我们已经证明了微环境/白血病相互作用在白血病干细胞的化疗耐药性中起着重要作用，SDF-1a/CXCR 4轴是这种相互作用的关键调节因子。我们最近发现索拉非尼是一种极好的FLT 3-ITD抑制剂，具有高临床单药活性，包括I期研究中的完全缓解1，2。高CXCR 4水平与不良预后相关4，FLT 3突变上调CXCR 45。我们最近报道了用FDA批准的CXCR 4抑制剂AMD 3100（普乐沙法）的类似物抑制CXCR 4导致白血病细胞的动员和对索拉非尼6的促凋亡作用的敏化。G-CSF切割SDF-1，下调CXCR 4，被发现在动员造血干细胞中与AMD 3100高度协同9，并且最近被FDA批准。我们已经报道了接受AMD 3100/G-CSF治疗的缓解期AML患者，AML细胞大量流出到循环中，为白血病细胞动员提供了第一个原则证据10。此外，我们在CR的AML患者和接受AMD 3100/G-CSF作为准备方案的一部分随后接受SCT的活动性疾病患者中观察到AML相对于正常细胞的优先动员，进一步支持了这种治疗概念的有效性。值得注意的是，索拉非尼对正常造血细胞没有毒性。基于这些发现，我们建议检验以下假设：在FLT 3突变型AML患者中，通过AMD 3100/G-CSF破坏SDF-1a/CXCR 4动员白血病干细胞可改善索拉非尼的抗白血病活性。此外，我们将研究这种靶向治疗对非动员AML母细胞的影响。我们将进行一项临床试验，以确定AMD 3100、G-CSF和递增剂量的FLT 3-ITD抑制剂索拉非尼在携带FLT 3-ITD突变的AML患者中的安全性和疗效，并研究AMD 3100/G-CSF破坏SDF-1a/CXCR 4相互作用的体内生物学效应。具有FLT 3-ITD突变的患者可以具有可变数量的具有三种不同FLT 3基因型的细胞：杂合FLT 3-ITD、纯合FLT 3-ITD和野生型FLT 3。因此，我们还将通过单细胞PCR确定在用AMD 3100/G-CSF动员期间和用索拉非尼治疗后，该疗法对携带这些基因型的细胞的影响。综上所述，这些研究将确定AMD 3100/G-CSF/索拉非尼的安全性和抗白血病活性，并对白血病细胞动员和细胞信号传导抑制相关机制进行全面评估。 公共卫生相关性：急性骨髓性白血病是一种主要致命的疾病，特别是在白血病细胞以FLT 3基因突变为特征的患者中。我们最近发现，FDA批准用于某些其他癌症的药物索拉非尼是携带这种突变的细胞的极好抑制剂，导致血液中白血病细胞的完全清除和骨髓白血病细胞的减少。我们建议在携带FLT 3-ITD突变的复发性/难治性AML患者中进行一项临床试验，将联合收割机索拉非尼与趋化因子受体CXCR 4阻滞剂AMD 3100（普乐沙福）联合使用，以确定该方法的安全性和有效性。