TARGETING THE CXCR4-SDF1 AXIS AS THERAPY FOR RELAPSED/REFRACTORY AML

靶向 CXCR4-SDF1 轴作为复发/难治性 AML 的治疗方法

• 批准号: 7751268
• 负责人: John F. Dipersio
• 金额: $ 33.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751268
• 关键词: AMD3100; Acute Myelocytic Leukemia; Allogenic; Apoptosis; Ara-C; Autologous; Binding; Biological Assay; Biology; Blast Cell; Bone Marrow; Bone Marrow Stem Cell; CD34 gene; CD44 gene; CXCR4 gene; Cell Adhesion Molecules; Cell Cycle; Cells; Chemotaxis; Chemotherapy-Oncologic Procedure; Clinical Research; Clinical Trials; Complement 3d Receptors; Cytolysis; Data; Dose; Epigenetic Process; Etoposide; Flow Cytometry; Future; Genetic; Genotoxic Stress; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Mobilization; Homing; Human; IL3RA gene; In Vitro; In complete remission; Integrin alpha4beta1; Interruption; Kinetics; Leukostasis; Ligands; Light; Measures; Mitoxantrone; Nature; Osteoblasts; Outcome; Patients; Phase; Phenotype; Play; Recovery; Refractory; Relapse; Resistance; Role; Safety; Scheme; Signal Transduction; Staging; Stem cell transplant; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Surface; Surrogate Endpoint; Testing; Toxic effect; bicyclam; chemotherapy; clinically significant; design; human subject; improved; in vitro Assay; in vivo; inhibitor/antagonist; insight; leukemia; leukemic stem cell; novel strategies; outcome forecast; peripheral blood; phase 1 study; pre-clinical; protective effect; public health relevance; receptor; reconstitution; resistance factors; response; small molecule; tumor

DESCRIPTION (provided by applicant): Patients with relapsed acute myelogenous leukemia (AML) have a uniformly grim prognosis; only 13-40% achieves a complete response (CR) with currently available salvage chemotherapy regimens. Long-term survival can only be achieved by those who proceed to an allogeneic or autologous stem cell transplant after achieving a CR2. In spite of advances in our understanding of the biology of both AML and relapsed AML, there have been no significant improvements in either treatments or outcomes in the past 10-20 years. This suggests the need for new approaches to overcome inherent biologic resistance of relapsed AML. We hypothesize that targeting the interaction of AML with the bone marrow (BM) microenvironment will overcome the acquired resistance factors inherent in relapsed AML and result in improved CR rates and overall outcomes. We and others have shown that the BM microenvironment provides an important protective effect against genotoxic stresses such as chemotherapy and that physical interruption of this interaction render AML cells sensitive to chemotherapy in vitro and in vivo. We propose to target the CXCR4-SDF-1 axis using a small molecule bicyclam, AMD3100, to promote rapid release of AML blasts from the BM microenvironment in patients with relapsed AML. In Aim 1 we will perform a phase I/II clinical trial in patients with relapsed AML. AMD3100 will be administered immediately prior to mitoxantrone-etoposide-high dose Ara-C (MEC) salvage chemotherapy, thus sensitizing the AML blasts to MEC chemotherapy. We will assess the safety and toxicities of AMD3100, its impact on multi-lineage hematopoietic recovery and, most importantly, on CR rates. In Aim 2 we will measure the magnitude and kinetics of AML mobilization after AMD3100 administration and attempt to characterize the phenotype, surface CXCR4 expression and cell cycle status of AML blasts and primitive (CD34?) subsets of AML before and after AMD3100 treatment. In Aim 3 we will functionally assess the impact of AMD3100 on mobilizing Leukemia Stem Cells (LSCs) using in vitro LTC-IC and in vivo NOD-SCID repopulating cell (SRC) assays. Finally, we will use two separate informative in vitro assays (chemotaxis and intracellular Ca flux) as surrogate endpoints for SDF-1 signaling to determine if SDF-1 signaling is dysregulated in AML blasts after AMD3100 induced mobilization. These studies will provide insights on the effect of disrupting AML-BM microenvironment interactions using AMD3100 and other small molecules in the future. This approach may represent a simple and non-toxic way of increasing chemotherapy sensitivity and overcoming inherent genetic and epigenetic resistance factors associated with AML thus improving outcomes of patients with relapsed and resistant AML. PUBLIC HEALTH RELEVANCE: We will use a rapid stem cell mobilizing agent, AMD3100 to pharmacologically detach leukemic stem cells from the bone marrow thus sensitizing them to chemotherapy. This will be used to treat patients with relapsed AML to improve outcomes.

描述（由申请人提供）：复发性急性髓性白血病（AML）患者的预后均十分严峻；使用目前可用的挽救性化疗方案，只有 13-40% 的患者达到完全缓解 (CR)。只有在获得 CR2 后进行同种异体或自体干细胞移植的患者才能实现长期生存。尽管我们对 AML 和复发性 AML 的生物学了解有所进展，但在过去 10-20 年中，治疗方法或结果均没有显着改善。这表明需要新的方法来克服复发性 AML 固有的生物耐药性。我们假设，针对 AML 与骨髓 (BM) 微环境的相互作用将克服复发性 AML 固有的获得性耐药因素，并提高 CR 率和总体结果。我们和其他人已经证明，BM 微环境对化疗等基因毒性应激具有重要的保护作用，并且这种相互作用的物理中断使 AML 细胞对体外和体内化疗敏感。我们建议使用小分子双环酰胺 AMD3100 靶向 CXCR4-SDF-1 轴，以促进复发性 AML 患者的 BM 微环境中 AML 母细胞的快速释放。在目标 1 中，我们将对复发性 AML 患者进行 I/II 期临床试验。 AMD3100 将在米托蒽醌-依托泊苷-高剂量 Ara-C (MEC) 挽救化疗之前立即给药，从而使 AML 母细胞对 MEC 化疗敏感。我们将评估 AMD3100 的安全性和毒性、其对多谱系造血恢复的影响，最重要的是对 CR 率的影响。在目标 2 中，我们将测量 AMD3100 给药后 AML 动员的程度和动力学，并尝试表征 AMD3100 治疗前后 AML 母细胞和原始 (CD34?) AML 子集的表型、表面 CXCR4 表达和细胞周期状态。在目标 3 中，我们将使用体外 LTC-IC 和体内 NOD-SCID 再生细胞 (SRC) 检测功能评估 AMD3100 对动员白血病干细胞 (LSC) 的影响。最后，我们将使用两个独立的信息性体外测定（趋化性和细胞内 Ca 通量）作为 SDF-1 信号传导的替代终点，以确定 AMD3100 诱导动员后 AML 母细胞中 SDF-1 信号传导是否失调。这些研究将为未来使用 AMD3100 和其他小分子破坏 AML-BM 微环境相互作用的效果提供见解。这种方法可能代表了一种简单且无毒的方法，可以提高化疗敏感性并克服与 AML 相关的固有遗传和表观遗传耐药因素，从而改善复发性和耐药性 AML 患者的预后。公共健康相关性：我们将使用快速干细胞动员剂 AMD3100 通过药理学将白血病干细胞从骨髓中分离出来，从而使它们对化疗敏感。这将用于治疗复发性 AML 患者以改善预后。