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

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

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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

核心3的主要目标是为孢子提供所需的基础架构和专业知识开发，验证和实施对患者样品和异种移植人类的分子生物标志物测试白血病。这些测试将用于表征从患者获得的髓样肿瘤的反应和针对目标疗法的临床前模型在每个项目中都在测试。核心由乔恩·C（Jon C.）博士领导。阿特（Aster），白血病高级研究员和实践血液病理学家。测试将以核心意愿进行包括量规NPM1和DNMT3A突变状态（项目1），SYK激活（项目2），编码剪接组件和SF3B1抑制的基因的突变状态（项目3）和免疫检查点蛋白的表达（项目4）。核心还将执行串行NextGen测序确定靶向疗法对克隆动力学的影响，并开发新的测试来评估肿瘤细胞对凋亡的敏感性（BH3分析/线粒体启动），或预测和衡量肿瘤细胞对SYK抑制剂，MENIN/MLL抑制剂和其他靶向疗法的反应。核心的具体目的是： 1）使用经过临床验证的基于扩增子的NextGen测序测试来识别突变，请定义克隆异质性，并遵循治疗过程中髓样肿瘤的克隆进化 2）开发，验证和实施对磷酸合并，免疫检查点蛋白的测试，谱系 - 特定的宿主免疫细胞标记和其他蛋白质生物标志物 3）开发，验证和实施基于RNA分析的测试，以识别有效的签名用新型治疗剂（包括剪接）靶向白血病信号通路抑制剂和Menin/MLL抑制剂 4）开发，验证和实施BH3分析/线粒体启动测定法以预测髓样肿瘤对靶向治疗的反应