TARGETING AML-STROMAL INTERACTIONS

针对 AML-间质相互作用

• 批准号: 8114266
• 负责人: John F. Dipersio
• 金额: $ 49.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-11 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114266
• 关键词: AMD3100; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Aftercare; Allogenic; Apoptosis; Ara-C; B-Cell Acute Lymphoblastic Leukemia; Binding; Biological Assay; Biology; Blast Cell; Bone Marrow; CD34 gene; CSF3 gene; CXCR4 gene; Cell Adhesion Molecules; Cell Cycle; Cell Transplants; Cells; Chemotaxis; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Complement 3d Receptors; Critical Pathways; Cytolysis; Disease; Disease Progression; Disease remission; Disease-Free Survival; Dose; E-Selectin; Epigenetic Process; Etoposide; FDA approved; Flow Cytometry; Future; Genetic; Genotoxic Stress; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Homing; Human; In Vitro; In complete remission; Integrin alpha4beta1; Interruption; Kinetics; Leukemic Cell; Leukostasis; Ligands; Measures; Mitoxantrone; Modeling; Molecular Abnormality; Mus; Normal Cell; Osteoblasts; Outcome; Pathway interactions; Patients; Phase; Phenotype; Play; Pre-Clinical Model; Recovery; Refractory; Refractory Disease; Regimen; Relapse; Resistance; Role; Safety; Scheme; Selectins; Signal Transduction; Staging; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Testing; Toxic effect; Vascular Cell Adhesion Molecule-1; bicyclam; chemotherapy; clinically significant; experience; improved; in vivo; inhibitor/antagonist; innovation; insight; leukemia; leukemic stem cell; mouse model; novel; novel strategies; outcome forecast; phase 1 study; protective effect; receptor; reconstitution; resistance factors; response; safety testing; small molecule; stem; trafficking; 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/CRi) with currently available salvage chemotherapy regimens. Long-term survival can only be achieved by those who proceed to an allogeneic 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 innovative 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 in conjunction with Granulocyte Colony Stimulating Factor (G-CSF), to promote rapid and sustained 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. G-CSF+AMD3100 will be administered prior to mitoxantrone-etoposide-high dose Ara-C (MEC) salvage chemotherapy to optimally mobilize leukemic blasts, thus sensitizing the AML blasts to MEC chemotherapy. We will assess the safety and toxicities of G- CSF+AMD3100, their impact on multi-lineage hematopoietic recovery and, most importantly, on CR rates. In Aim 2 we will measure the magnitude of AML mobilization after G-CSF +AMD3100 administration and attempt to characterize the phenotype and cell cycle status of AML blasts and primitive (CD34+/CD38-) subsets of AML before and after G-CSF+AMD3100 treatment. In addition we will functionally assess the impact of G- CSF+AMD3100 on mobilizing Leukemia Stem Cells (LSCs) using in vitro LTC-IC and in vivo NOD-SCID repopulating cell (SRC) assays. In Aim 3 we will use a novel and informative models of mouse AML and human ALL to explore the role of small molecule inhibitors of two other critical axes (VLA-4/VCAM-1 and Selectin/Selectin Ligand) on normal and leukemia stem cell mobilization and homing to the BM. The effects of these small molecules will be tested alone or in combination with CXCR4 blocking agents (AMD3100, 070, G- CSF and ALT1188). VLA-4 and pan-selectin inhibitors will be used in these models alone or in combination to determine if they also can be used to sensitize leukemic cells to chemotherapy in vivo. These studies will provide insights on the effect of disrupting AML-BM microenvironment interactions using AMD3100, G-CSF 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: Acute myelogenous leukemia (AML) represents a diverse group of diseases with diverse genetic and epigenetic abnormalities. Prognosis of patients who relapse or who have refractory disease is dismal. New approaches are needed which both target genetic abnormalities associated with initiation and progression of the disease and interrupt common pathways that support the survival and quiescent state of leukemic cells. We propose to use G-CSF plus AMD3100 as well as other novel small molecule inhibitors of three critical pathways associated with homing of AML blasts to the bone marrow thus rendering these cells more sensitive to chemotherapy. We hypothesize that pharmacologic interruption of the tethers that bind AML blasts to the bone marrow will sensitize these cells to chemotherapy and improve remission rates and long term disease free survival.

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/CRi)。只有在获得 CR2 后进行同种异体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。这表明需要创新的新方法来克服复发性 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 与粒细胞集落刺激因子 (G-CSF) 联合靶向 CXCR4-SDF-1 轴，以促进复发性 AML 患者的 BM 微环境中快速、持续释放 AML 母细胞。在目标 1 中，我们将对复发性 AML 患者进行 I/II 期临床试验。 G-CSF+AMD3100 将在米托蒽醌-依托泊苷-高剂量 Ara-C (MEC) 挽救化疗之前施用，以最佳地动员白血病母细胞，从而使 AML 母细胞对 MEC 化疗敏感。我们将评估 G-CSF+AMD3100 的安全性和毒性、它们对多系造血恢复的影响，最重要的是对 CR 率的影响。在目标 2 中，我们将测量 G-CSF + AMD3100 给药后 AML 动员的程度，并尝试表征 G-CSF + AMD3100 前后 AML 母细胞和原始 (CD34+/CD38-) AML 子集的表型和细胞周期状态治疗。此外，我们将使用体外 LTC-IC 和体内 NOD-SCID 再生细胞 (SRC) 测定，从功能上评估 G-CSF+AMD3100 对动员白血病干细胞 (LSC) 的影响。在目标 3 中，我们将使用小鼠 AML 和人类 ALL 的新颖且信息丰富的模型来探索其他两个关键轴（VLA-4/VCAM-1 和选择素/选择素配体）的小分子抑制剂对正常和白血病干细胞的作用动员并归航至 BM。这些小分子的效果将单独或与 CXCR4 阻断剂（AMD3100、070、G-CSF 和 ALT1188）组合进行测试。 VLA-4和泛选择素抑制剂将单独或组合用于这些模型，以确定它们是否也可用于使白血病细胞对体内化疗敏感。这些研究将为未来使用 AMD3100、G-CSF 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。 公共卫生相关性：急性髓性白血病 (AML) 代表具有多种遗传和表观遗传异常的多种疾病。复发或患有难治性疾病的患者的预后很差。需要新的方法，既要针对与疾病发生和进展相关的遗传异常，又要中断支持白血病细胞存活和静止状态的常见途径。我们建议使用 G-CSF 加 AMD3100 以及其他新型小分子抑制剂，抑制与 AML 母细胞归巢至骨髓相关的三个关键途径，从而使这些细胞对化疗更加敏感。我们假设，药物阻断将 AML 母细胞与骨髓结合的系绳将使这些细胞对化疗敏感，并提高缓解率和长期无病生存率。