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/白血病相互作用在白血病干细胞的化疗耐药性中发挥着重要作用，并且 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出色的 FLT3-ITD 抑制剂，具有很高的临床单药活性，包括在 I 期研究中完全缓解1,2。高 CXCR4 水平与不良预后相关4，而 FLT3 突变会上调 CXCR45。我们最近报道，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并对索拉非尼6的促凋亡作用敏感。 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协同作用9，最近获得 FDA 批准。我们报道过，接受 AMD3100/G-CSF 治疗的缓解期 AML 患者有大量 AML 细胞进入循环系统，这为白血病细胞动员提供了第一个原理证明10。此外，我们观察到 AML 比正常细胞优先动员，无论是在 CR 的 AML 患者中，还是在接受 AMD3100/G-CSF 作为准备方案一部分并随后接受 SCT 的活动性疾病患者中，这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 破坏 SDF-1a/CXCR4 来动员白血病干细胞，可提高索拉非尼在具有突变 FLT3 的 AML 患者中的抗白血病活性。此外，我们还将研究这种靶向治疗对非动员的 AML 母细胞的影响。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 抑制剂索拉非尼对携带 FLT3-ITD 突变的 AML 患者的安全性和有效性，并研究破坏 SDF-1a/ 的体内生物学效应。 AMD3100/G-CSF 与 CXCR4 相互作用。具有FLT3-ITD突变的患者可以具有不同数量的具有三种不同FLT3基因型的细胞：杂合子FLT3-ITD、纯合子FLT3-ITD和野生型FLT3。因此，我们还将通过单细胞 PCR 确定该疗法在 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。总而言之，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，并对涉及白血病细胞动员和细胞信号传导抑制的机制提供全面评估。