Project 1: Clonal Dynamics Guiding Curative Therapies for Acute Myeloid Leukemia

项目 1：克隆动力学指导急性髓系白血病的治疗

• 批准号: 8866712
• 负责人: David T Scadden
• 金额: $ 51.05万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8866712
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Algorithms; Alleles; Anatomy; Animal Model; Animals; Apoptosis; Behavior; Bioinformatics; Biological Sciences; Blood; Bone Marrow; Brain; Breast; Cancer Biology; Cell Count; Cell Cycle; Cells; Clinical Trials; Cytotoxic Chemotherapy; Data; Data Set; Development; Dimensions; Disease; Disease remission; Engineering; Event; Evolution; Experimental Models; Flow Cytometry; Fostering; Gene Expression Profile; Generations; Genetic; Genomics; Growth; Hematologic Neoplasms; Heterogeneity; Human; Image; Imaging technology; Individual; Intervention; Lead; Lesion; Leukemic Cell; Location; Malignant Neoplasms; Maps; Measures; Mediating; Methodology; Methods; Modeling; Molecular; Mus; Outcome; Pathway interactions; Patients; Phenotype; Population; Positioning Attribute; Refractory; Relapse; Relative (related person); Research Personnel; Resistance; Resolution; Role; Signal Transduction; Solid Neoplasm; Testing; Time; Whole Organism; abstracting; base; cancer cell; cancer type; cell killing; chemotherapy; disorder control; genetic evolution; human FRAP1 protein; improved; in vivo; killings; leukemia; mathematical model; mouse model; novel; novel strategies; physical science; research study; response; targeted treatment; therapy resistant; tool; treatment response; treatment strategy; tumor

Project Summary / Abstract Acute myeloid leukemia (AML) is rapidly fatal, poorly controlled disease that can be rapidly brought into complete remission but where relapse kills the vast majority of patients. The genetic evolution of the disease has been defined retrospectively, but the basis for resistance to therapy and effective strategies to overcome it are lacking. This project seeks to take advantage of well-defined mouse models where a human leukemogenic allele induces highly penetrant, lethal AML that can be temporarily brought into remission by chemotherapy agents used in patients. Combining these basic biologic features with novel strategies for quantitatively assessing clonal behavior, clonal molecular features, physical localization and the in vivo parameters of growth pathway, cell cycle and apoptosis over time will provide multidimensional datasets for mathematical modeling of the parameters correlating with: 1. Clonal dominance in vivo (Specific Aim 1) and, 2. Sensitivity/resistance to chemotherapy in vivo (Specific Aim 2). The models will guide experimental testing of the role of the parameters in the in vivo behavior of the disease that will then be used to develop and test methods for enhancing durable control of AML (Specific Aim 3).

项目摘要 /摘要 急性髓样白血病（AML）迅速致命，控制疾病不良，可以迅速带入 完全缓解，但复发会杀死绝大多数患者。疾病的遗传进化 已被追溯定义，但要对治疗的抵抗和有效策略克服的基础 缺乏。该项目旨在利用人类白血病的定义明确的小鼠模型 等位基因诱导高度渗透性，致命的AML，可以通过化学疗法暂时缓解 药物用于患者。将这些基本的生物学特征与新颖的策略相结合 评估克隆行为，克隆分子特征，物理定位和生长的体内参数 途径，细胞周期和随时间凋亡将为数学建模提供多维数据集 与：1。体内克隆优势相关的参数（特定目标1）和2。对 体内化学疗法（特定目标2）。模型将指导实验测试 疾病的体内行为中的参数将用于开发和测试用于 增强对AML的持久控制（特定目标3）。