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: 8056055
• 负责人: MICHAEL ANDREEFF
• 金额: $ 31.22万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056055
• 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; Health; 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; 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.

描述(申请人提供)：携带Flt3基因突变的复发性急性髓系白血病(AML)患者的预后极差。我们已经证明，微环境/白血病的相互作用在白血病干细胞的化疗耐药中起着重要作用，SDF-1a/CXCR4轴是这种相互作用的关键调节因子。我们最近发现，索拉非尼是一种优秀的Flt3-ITD抑制剂，具有很高的临床单药活性，包括I期研究1，2的完全缓解。CXCR4水平高与不良预后相关4，Flt3突变上调CXCR45。我们最近报道了用FDA批准的CXCR4抑制剂AMD3100(Plerixafar)的类似物抑制CXCR4导致白血病细胞动员和对Sorafenib6的促凋亡作用增敏。G-CSF裂解SDF-1，下调CXCR4，被发现与AMD3100在动员造血干细胞方面具有高度的协同作用，最近被FDA批准。我们曾报道，接受AMD3100/G-CSF治疗的缓解期AML患者有大量AML细胞进入循环，这为白血病细胞动员提供了第一个原理证据。此外，我们观察到急性髓细胞白血病的优先动员高于正常细胞，无论是在CR的AML患者中，还是在接受AMD3100/G-CSF作为SCT后准备方案的一部分的活动期疾病患者中，进一步支持了这一治疗概念的有效性。值得注意的是，索拉非尼对正常的造血细胞没有毒性。基于这些发现，我们建议检验这样一种假设，即AMD3100/G-CSF通过破坏SDF-1a/CXCR4动员白血病干细胞可以改善具有突变Flt3的AML患者的索拉非尼的抗白血病活性。此外，我们还将研究这种靶向治疗对非动员AML细胞的影响。我们将进行一项临床试验，以确定AMD3100、G-CSF和递增剂量的Flt3-ITD抑制剂索拉非尼治疗携带Flt3-ITD突变的AML患者的安全性和有效性，并研究AMD3100/G-CSF干扰SDF-1a/CXCR4相互作用的体内生物学效应。携带Flt3-ITD突变的患者可以有数量不等的细胞，具有三种不同的Flt3基因类型：杂合的flt3-itd、纯合的flt3-itd和野生型。因此，我们还将通过单细胞聚合酶链式反应来确定这种疗法在AMD3100/G-CSF动员期间和索拉非尼治疗后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AMD3100/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抑制细胞信号的机制进行全面评估。