Targeting Leukemia Stromal Interactions in AML

描述(由申请者提供)：本职业发展建议旨在为申请者提供培训和支持，使其成为一名专注于急性髓系白血病(AML)生物学和治疗的独立翻译研究人员。这项建议的目标是1。在临床研究设计、解释临床研究结果的方法论方面获得教学培训。2.发展急性髓细胞白血病及其他血液系统恶性肿瘤的临床治疗经验。3.培养临床研究所需的“生存技能”，包括拨款和手稿写作、公开演讲、处理监管问题和促进有效合作。在急性髓细胞白血病中，白血病母细胞与骨髓微环境的相互作用可能会保护细胞免受自发凋亡和遗传毒性应激(如化疗)的影响。该项目的长期目标是确定和测试针对骨髓微环境保护效果的治疗方法。我们推测，通过破坏白血病间质的相互作用，我们将使AML对细胞毒化疗的效果敏感。尽管已发现许多候选受体-配体对，但CXCR4(在正常和白血病干细胞上表达)及其配体SDF-1(在骨髓基质细胞和成骨细胞上表达)在骨髓干细胞归巢和滞留中发挥核心作用。我们将在一项临床试验中测试CXCR4的小分子抑制剂AMD3100使急性髓细胞白血病化疗增敏的能力，该临床试验题为《AMD3100联合米托蒽醌、依托泊苷和阿糖胞苷治疗复发或难治性急性髓细胞白血病的L期研究(AMD3100-I-MEC)》。我们预测，像正常的HSCs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，以检测AMD3100对AML动员和CXCR4/SDF-1信号转导的影响。我们还将继续识别和测试调节白血病间质相互作用的替代途径。 相关性(见说明)：这项提议的目标是培养一名独立的内科科学家，从事翻译研究，专注于急性髓系白血病(AML)新疗法的开发。拟议的研究计划以骨髓微环境为靶点，以提高AML的治疗效果。

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.