Targeting Leukemia Stromal Interactions in AML

描述（由申请人提供）：该职业发展计划旨在为申请人提供培训和支持，使其成为专注于急性髓细胞白血病（AML）生物学和治疗的独立翻译研究人员。该提案的目标是1。获得临床研究设计、临床研究结果解释方法学方面的教学培训。2.发展AML和其他血液恶性肿瘤治疗的临床专业知识。3.培养临床研究所需的“生存技能”，包括赠款和手稿写作，公开演讲，导航监管问题，并促进有效的合作。在AML中，白血病原始细胞与骨髓微环境的相互作用可以保护免受自发性细胞凋亡和遗传毒性应激如化疗。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间质相互作用，我们将使AML对细胞毒性化疗的作用敏感。虽然许多候选受体-配体对已经被牵涉，但CXCR 4（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中发挥核心作用。我们将在名为“AMD 3100加米托蒽醌、依托泊苷和阿糖胞苷（AMD 3100-I-MEC）治疗复发性或难治性AML的I/II期研究”的临床试验中测试CXCR 4的小分子抑制剂AMD 3100对AML化疗增敏的能力。“我们预测，像正常的HSC一样，AMD 3100将动员AML患者的白血病母细胞。我们将进行相关研究，以检查AML动员和CXCR 4/ SDF-1信号转导对AMD 3100的反应。我们还将继续鉴定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）：该提案的目标是培养一名独立的医生-科学家，作为专注于开发急性髓性白血病（AML）新疗法的翻译研究人员。拟议的研究计划针对骨髓微环境，以提高AML治疗的有效性。

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.