Integrated high-throughput screen to identify treatment leads for pediatric AML

集成高通量筛选以确定儿童 AML 的治疗线索

基本信息

批准号：
8899473
负责人：
Christina Diane Drenberg
金额：
$ 5.8万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899473
关键词：
Accounting Acute Lymphocytic Leukemia Acute Megakaryocytic Leukemias Acute Myelocytic Leukemia Address Age Biological Blast Cell Cancer cell line Cell Density Cell Line Cells Chemicals Child Childhood Acute Myeloid Leukemia Childhood Leukemia Clinical Clinical Trials Collection Cytarabine Diagnosis Dimethyl Sulfoxide Disease Disease-Free Survival Dose Drug Combinations Epigenetic Process FDA approved FLT3 gene Future Goals Health Hematopoietic Histone Deacetylase Inhibitor Human In Vitro Laboratory Study Lead Libraries Malignant Childhood Neoplasm Malignant Neoplasms Modeling Mus Myeloid Progenitor Cells Newly Diagnosed Outcome Patients Pharmaceutical Preparations Phosphotransferases Positioning Attribute Publishing Refractory Regimen Relapse Saint Jude Children&apos s Research Hospital Sampling Source Specificity Survival Rate Testing Therapeutic Therapeutic Agents Toxic effect Transgenic Organisms Translating Treatment Efficacy Treatment Protocols Validation Xenograft procedure base c-myc Genes cohort conventional therapy design drug sensitivity effective therapy high throughput screening human disease improved in vivo in vivo Model insight kinase inhibitor mouse model novel novel therapeutics outcome forecast pharmacophore pre-clinical pre-clinical research response scaffold standard of care stem success therapeutic evaluation therapeutic target tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The management of pediatric cancers has seen significant progress in the past two decades, with some cancers (e.g., acute lymphoblastic leukemia) nearing 80-90% cure rates. Long-term survival rates in children with newly diagnosed acute myelogenous leukemia (AML) have recently improved from approximately 50% to 70% at St. Jude Children's Research Hospital. AML, which represents about 15% of all childhood leukemias, is a heterogeneous disease characterized by uncontrolled clonal proliferation of hematopoietic stem/progenitor cells of the myeloid lineage with reduced capacity to differentiate into mature cells. Preclinical research has been supplemented by laboratory studies of human cancer cell lines and xenograft mouse models aimed at identifying therapies. Although this approach has ascertained some novel therapeutics, it is inherently inefficient, often failing to account for the multitude of subtypes and providing little insight into the patients most likely to benefit from each therapy. The goal of this proposal is to address an unmet need to identify effective treatment strategies for children with AML. The underlying hypothesis is that high-throughput screening can predict efficacy and toxicity of novel therapeutics which will be effective for the treatment of childhood AML. To test this hypothesis, we propose the following specific aims: Specific Aim 1: To identify novel therapeutics for the treatment of pediatric AML using a high-throughput screen of over 8000 compounds. Specific Aim 2: To evaluate the efficacy of therapeutic leads identified by high-throughput screen using in vitro and in vivo models of AML in combination with cytarabine. Implementation of acute myeloid leukemia cell lines which represent subtypes with the poorest prognosis, in addition to primary blasts isolated from a c-Myc induced murine model of AML will recapitulate human disease. Furthermore, evaluation of therapeutics leads in combination with standard of care agents is a rational design to accelerate incorporation of new treatment strategies. The long-term goal of this project is to translate our preclinical findings to clinical trials at St. Jude, and ultimately improve the long-term outcome of children with AML.

描述（由申请人提供）：儿科癌症的治疗在过去二十年中取得了显着进展，一些癌症（例如急性淋巴细胞白血病）的治愈率接近 80-90%。圣裘德儿童研究医院新诊断的急性髓性白血病 (AML) 儿童的长期生存率最近从约 50% 提高到 70%。 AML 约占所有儿童白血病的 15%，是一种异质性疾病，其特征是骨髓系造血干细胞/祖细胞的克隆增殖不受控制，分化为成熟细胞的能力降低。人类癌细胞系和异种移植小鼠模型的实验室研究补充了临床前研究，旨在确定治疗方法。尽管这种方法已经确定了一些新的治疗方法，但它本质上效率低下，往往无法考虑多种亚型，并且无法深入了解最有可能接受治疗的患者。从每种疗法中受益。该提案的目标是解决未满足的需求，为患有 AML 的儿童确定有效的治疗策略。基本假设是，高通量筛选可以预测新疗法的功效和毒性，这些新疗法将有效治疗儿童 AML。为了检验这一假设，我们提出以下具体目标：具体目标 1：通过对 8000 多种化合物进行高通量筛选，确定治疗儿科 AML 的新疗法。具体目标 2：使用 AML 的体外和体内模型联合阿糖胞苷，评估通过高通量筛选确定的治疗先导药物的功效。除了从 c-Myc 诱导的 AML 小鼠模型中分离出的原代母细胞之外，使用代表预后最差的亚型的急性髓系白血病细胞系将重现人类疾病。此外，对治疗药物的评估与标准护理药物相结合是加速新治疗策略纳入的合理设计。该项目的长期目标是将我们的临床前研究结果转化为圣裘德的临床试验，并最终改善 AML 儿童的长期结果。