Targeting Leukemia Stromal Interactions in AML

靶向 AML 中的白血病基质相互作用

• 批准号: 8474710
• 负责人: GEOFFREY L UY
• 金额: $ 15.89万
• 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: 2009-09-14 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8474710
• 关键词: AMD3100; Acute Myelocytic Leukemia; Adverse event; Apoptosis; Biological Assay; Biology; Blast Cell; Blood Circulation; Bone Marrow; CSF3 gene; CXCR4 gene; Cell Adhesion Molecules; Cell physiology; Chemotaxis; Clinical; Clinical Research; Clinical Trials; Collaborations; Correlative Study; Cytarabine; Cytotoxic Chemotherapy; Development; Dose; Etoposide; Event; Flow Cytometry; Genotoxic Stress; Goals; Grant; Hematologic Neoplasms; Hematopoietic stem cells; Homing; Human; Immunodeficient Mouse; Immunophenotyping; Instruction; Integrin alpha4beta1; Ligands; Manuscripts; Marrow; Measures; Mediating; Methodology; Mitoxantrone; Modeling; Mus; Osteoblasts; Pathway interactions; Patients; Peripheral; Phase; Physicians; Play; Public Speaking; Recovery; Refractory; Relapse; Research; Research Design; Research Personnel; Role; Safety; Scientist; Signal Transduction; Staging; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Surface; Testing; Time; Toxic effect; Training; Training Support; Treatment Effectiveness; Vascular Cell Adhesion Molecule-1; Writing; Xenograft procedure; career; career development; chemotherapy; design; improved; inhibitor/antagonist; leukemia; leukemic stem cell; novel; phase 1 study; preclinical study; protective effect; receptor; research study; response; skills; small molecule

DESCRIPTION (provided by applicant): This career development proposal is designed to provide training and support for the applicant to become an independent translational researcher focused on the biology and treatment of acute myeloid leukemia (AML). The goals of this proposal are to 1. To obtain didactic training in clinical research design, methodology for interpreting results of clinical research studies. 2. To develop clinical expertise in the treatment of AML and other hematologic malignancies. 3. To develop the "survival skills" necessary in clinical research including grant and manuscript writing, public speaking, navigating regulatory issues, and promoting effective collaborations. In AML, interaction of leukemic blasts with the bone marrow microenvironment may protect against spontaneous apoptosis and genotoxic stresses such as chemotherapy. The long term goal of this project is to identify and test therapies which target the protective effect of the marrow microenvironment. We hypothesize that by disrupting leukemia stromal interactions we will sensitize AML to the effects of cytotoxic chemotherapy. Although many candidate receptor-ligand pairs have been implicated, CXCR4 (expressed on normal and leukemic stem cells), and its ligand SDF-1 (expressed on BM stromal cells and osteoblasts) play a central role in stem cell homing and retention in the BM. We will test the ability of AMD3100, a small molecule inhibitor of CXCR4, to chemosensitize AML in a clinical trial entitled, "A phase l/ll study of AMD3100 plus mitoxantrone, etoposide, and cytarabine (AMD3100-I-MEC) in relapsed or refractory AML." We predict that like normal HSCs, AMD3100 will mobilize leukemic blasts in patients with AML. We will perform correlative studies to examine AML mobilization and alterations in CXCR4 / SDF-1 signaling in response to AMD3100. We will also continue to identify and test alternative pathways which mediate leukemia stromal interactions. RELEVANCE (See instructions): The goal of this proposal is to train an independent physician-scientist for a career as a translational researcher focused on the development of novel therapies for acute myeloid leukemia (AML). The proposed research plans to target the bone marrow microenvironment to improve the effectiveness of treatment of AML.

描述（由申请人提供）：本职业发展提案旨在为申请人提供培训和支持，使其成为专注于急性髓系白血病（AML）生物学和治疗的独立转化研究人员。本提案的目标是 1. 获得临床研究设计、解释临床研究结果的方法方面的教学培训。 2. 发展治疗 AML 和其他血液恶性肿瘤的临床专业知识。 3. 培养临床研究所需的“生存技能”，包括资助和稿件撰写、公开演讲、解决监管问题以及促进有效合作。在 AML 中，白血病母细胞与骨髓微环境的相互作用可以防止自发性细胞凋亡和化疗等基因毒性应激。该项目的长期目标是确定和测试针对骨髓微环境保护作用的疗法。我们假设，通过破坏白血病基质相互作用，我们将使 AML 对细胞毒性化疗的作用敏感。尽管涉及许多候选受体-配体对，但 CXCR4（在正常和白血病干细胞上表达）及其配体 SDF-1（在 BM 基质细胞和成骨细胞上表达）在干细胞归巢和保留在 BM 中发挥着核心作用。我们将在一项题为“AMD3100 加米托蒽醌、依托泊苷和阿糖胞苷 (AMD3100-I-MEC) 治疗复发或复发性白血病的 l/ll 期研究 (AMD3100-I-MEC)”的临床试验中测试 AMD3100（CXCR4 的小分子抑制剂）对 AML 进行化疗增敏的能力。难治性 AML。”我们预测，与正常 HSC 一样，AMD3100 将动员 AML 患者的白血病原始细胞。我们将进行相关研究，以检查 AML 动员和 CXCR4 / SDF-1 信号转导对 AMD3100 的反应。我们还将继续识别和测试介导白血病基质相互作用的替代途径。 相关性（参见说明）：本提案的目标是培养一名独立的医师科学家，从事转化研究人员的职业，专注于开发急性髓系白血病 (AML) 的新疗法。拟议的研究计划以骨髓微环境为目标，以提高 AML 治疗的有效性。

项目成果

Targeting the microenvironment in acute myeloid leukemia.

• DOI: 10.1007/s11899-015-0255-4
• 发表时间: 2015-06
• 期刊: CURRENT HEMATOLOGIC MALIGNANCY REPORTS
• 影响因子: 2.9
• 作者: Rashidi, Armin;Uy, Geoffrey L.
• 通讯作者: Uy, Geoffrey L.

Plasmacytoma-like post-transplantation lymphoproliferative disease occurring in a cardiac allograft: a case report and review of the literature.

心脏同种异体移植物中发生的浆细胞瘤样移植后淋巴增殖性疾病：病例报告和文献综述。

• DOI: 10.1200/jco.2011.39.5855
• 发表时间: 2012
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Wang,Tzu-Fei;Klein,JonathanL;Woodard,PamelaK;Hassan,Anjum;Joseph,SusanM;Ewald,GregoryA;Uy,GeoffreyL
• 通讯作者: Uy,GeoffreyL