权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CORRELATIVE SCIENCE CORE

基本信息

批准号：
10220874
负责人：
JON C. ASTER
金额：
$ 2.05万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220874
关键词：
Acute Myelocytic Leukemia Apoptosis Biological Assay Biostatistics Core CLIA certified Cancer Center Cells Clinical Clonal Evolution Data Development Diagnosis Environment Genes Goals HRX protein Heterogeneity Histopathology Human Immune Infrastructure Menin Mitochondria Mutation Myeloproliferative disease NPM1 gene Patients Pre-Clinical Model Proteins RNA Reproduction spores Research Personnel SYK gene Sampling Science Sensitivity and Specificity Services Signal Pathway Specialized Center Spliceosomes Testing Therapeutic Agents Translating Work Xenograft procedure base design immune checkpoint inhibitor/antagonist innovation leukemia molecular marker mutational status neoplastic cell next generation sequencing novel therapeutics predicting response protein biomarkers research clinical testing response success targeted treatment

项目摘要

The major goals of Core 3 are to provide the SPORE with the infrastructure and professional expertise needed to develop, validate, and implement molecular biomarker tests on patient samples and xenografted human leukemias. These tests will be used to characterize the response of myeloid neoplasms obtained from patients and preclinical models to targeted therapies being tested in each of the projects. The Core is led by Dr. Jon C. Aster, a senior leukemia investigator and practicing hematopathologist. Tests will be carried out in the Core will include assays that gauge NPM1 and DNMT3A mutational status (Project 1), SYK activation (Project 2), mutational status of genes encoding spliceasome components and SF3B1 inhibition (Project 3), and the expression of immune checkpoint proteins (Project 4). The Core will also perform serial NextGen Sequencing to determine the effect of targeted therapy on clonal dynamics, and develop new tests that assess the sensitivity of tumor cells to apoptosis (BH3 profiling/mitochondrial priming), or that predict and gauge the response of neoplastic cells to SYK inhibitors, Menin/MLL inhibitors, and other targeted therapeutics. The specific aims of the Core are: 1) To use a clinically validated amplicon-based NextGen sequencing test to identify mutations, define clonal heterogeneity, and follow the clonal evolution of myeloid neoplasms during therapy 2) To develop, validate, and implement tests for phospho-SYK, immune checkpoint proteins, lineage- specific host immune cell markers, and other protein biomarkers 3) To develop, validate, and implement RNA profiling-based tests that identify signatures of effective targeting of leukemogenic signaling pathways with novel therapeutic agents, including spliceasome inhibitors, and Menin/MLL inhibitors 4) To develop, validate, and implement a BH3 profiling/mitochondrial priming assay to predict the response of myeloid neoplasms to targeted therapeutics

Core 3的主要目标是为SPORE提供所需的基础设施和专业知识开发，验证和实施对患者样本和异种移植人的分子生物标志物测试白血病这些检测将用于描述从患者中获得的骨髓肿瘤的反应和临床前模型的靶向治疗正在测试中的每一个项目。核心由Jon C博士领导。高级白血病研究员和执业血液病理学家。测试将在核心区进行，包括测定NPM 1和DNMT 3A突变状态（项目1）、SYK激活（项目2）编码剪接体组分和SF 3B 1抑制的基因的突变状态（项目3），以及免疫检查点蛋白的表达（项目4）。核心还将执行系列NextGen测序确定靶向治疗对克隆动力学的影响，并开发评估克隆动力学的新测试肿瘤细胞对凋亡的敏感性（BH 3谱/线粒体引发），或预测和衡量肿瘤细胞对凋亡的敏感性。肿瘤细胞对SYK抑制剂、Menin/MLL抑制剂和其他靶向治疗剂的反应。该核心的具体目标是： 1)为了使用临床验证的基于扩增子的NextGen测序检测来识别突变，定义克隆异质性，并在治疗期间跟踪髓系肿瘤的克隆演变 2)开发、验证和实施磷酸化SYK、免疫检查点蛋白、谱系- 特异性宿主免疫细胞标志物和其它蛋白质生物标志物 3)开发，验证和实施基于RNA分析的测试，以识别有效的用包括剪接体在内的新治疗剂靶向致白血病信号通路抑制剂和Menin/MLL抑制剂 4)开发、验证和实施BH 3分析/线粒体引发试验，以预测髓系肿瘤对靶向治疗的反应