Targeting Leukemia Stromal Interactions in AML

描述（由申请人提供）：本职业发展计划旨在为申请人提供培训和支持，使其成为一名专注于急性髓性白血病（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、临床研究结果解释方法的教学培训。2. 发展AML和其他血液系统恶性肿瘤治疗的临床专业知识。3. 培养临床研究中必要的“生存技能”，包括拨款和手稿写作、公开演讲、解决监管问题和促进有效合作。在AML中，白血病母细胞与骨髓微环境的相互作用可能防止自发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治疗方法。我们假设，通过破坏白血病间质相互作用，我们将使AML对细胞毒性化疗的影响敏感。尽管许多候选受体-配体对都涉及到，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）在骨髓干细胞的归巢和保留中起着核心作用。我们将在一项名为“AMD3100联合米托蒽酮、依托oposide和阿糖胞苷（AMD3100- i - mec）治疗复发或难治性AML的l/ll期研究”的临床试验中测试AMD3100 （CXCR4的一种小分子抑制剂）对AML化学增敏的能力。我们预测，与正常造血干细胞一样，AMD3100将动员AML患者的白血病原细胞。我们将进行相关研究，以检测AML的动员和CXCR4 / SDF-1信号的改变对AMD3100的反应。我们还将继续确定和测试介导白血病基质相互作用的替代途径。

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.