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（由申请人提供）：携带FLT3突变的急性髓样白血病（AML）的患者的预后非常差。我们已经证明，微环境/白血病相互作用在白血病干细胞的化学耐药性中起主要作用，并且SDF-1A/CXCR4轴是这种相互作用的关键调节剂。我们最近发现，索拉非尼是一种具有较高临床单药活性的Superb FLT3-ITD抑制剂，包括在I期研究中完全缓解1,2。高CXCR4水平与预后不良相关，而FLT3突变上调CXCR45。我们最近报道说，用FDA认可的CXCR4抑制剂AMD3100（Plerixafar）的类似物对CXCR4的抑制作用导致动员白血病细胞，并对索拉非尼替尼的促凋亡作用进行敏感性。发现G-CSF切割SDF-1（下调CXCR4）在动员造血干细胞中与AMD3100高度协同作用，最近获得FDA批准。我们报告说，接受AMD3100/g-CSF治疗的缓解中的AML患者大量出口AML细胞进入循环系统，为白血病细胞动员的原理提供了第一证明。此外，我们观察到在CR的AML患者和活动疾病的患者中，AML患者在接受AMD3100/G-CSF的患者中，我们观察到AML的优先动员，作为制剂疗法的一部分，后者是SCT的一部分，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：通过AMD3100/G-CSF扰动SDF-1A/CXCR4动员白血病细胞，从而改善了索拉非尼的抗白血病活性在AML突变体FLT3患者中。此外，我们将研究这种靶向疗法对非动物AML爆炸的影响。我们将进行一项临床试验，以确定AMD3100，G-CSF的安全性和功效，并在AML携带FLT3-ITD突变的患者中的FLT3-ITD抑制剂Sorafenib的升级剂量升级，并研究了AMD3100/G-CSF的SDF-1A/CXCR4相互作用的破坏SDF-1A/CXCR4相互作用的体内生物学效应。患有FLT3-ITD突变的患者可以具有三种不同的FLT3基因型的细胞数量可变：杂合FLT3-ITD，纯合FLT3-ITD和野生型FLT3。因此，我们还将通过单细胞PCR来确定该疗法对携带这些基因型的细胞的作用，在用AMD3100/g-CSF动员过程中，并在用索拉非尼治疗后。综上所述，这些研究将确定AMD3100/G-CSF/Sorafenib的安全性和抗白血病活性，并对参与白血病细胞动员和抑制细胞信号传导的机制进行全面评估。