Trajectory and Architecture of Microenvironment-Mediated Resistance in AML

AML 中微环境介导的耐药性的轨迹和结构

基本信息

批准号：
10517761
负责人：
Anupriya Agarwal
金额：
$ 36.96万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2017-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517761
关键词：
ATAC-seq Acute Myelocytic Leukemia Address Aftercare Architecture BCL2 gene Biology Bone Marrow CRISPR screen Cell Line Cell Survival Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Combined Modality Therapy Communication Complex DNA sequencing Data Data Set Development Drug Combinations Drug Sensitization Drug resistance Engineering Environment Epigenetic Process Event Evolution Exposure to FGF2 gene FLT3 gene FLT3 inhibitor Flow Cytometry Funding Gene Expression Genetic Heterogeneity Goals Growth Growth Factor Heterogeneity Immune Immune Evasion Immune Targeting Immune signaling Immunofluorescence Immunologic Immunologic Factors Inflammatory Interleukin-1 JAK2 gene Leukemic Cell MEKs Malignant - descriptor Maps Mediating Medical Genetics Methylation Modeling Molecular Multiomic Data Mutation Natural Killer Cells Organoids Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Play Process Proteomics Recurrent disease Refractory Refractory Disease Relapse Residual state Resistance Role Route Sampling Screening Result Signal Pathway Signal Transduction Stress Stromal Cells T-Lymphocyte Testing Therapeutic Therapeutic Intervention acquired drug resistance acute myeloid leukemia cell base cancer cell cytokine data integration deep sequencing disorder control drug development drug sensitivity genome-wide improved inhibitor leukemia monocyte neoplastic cell network models new combination therapies novel novel therapeutic intervention predictive modeling progenitor resistance mechanism response screening single-cell RNA sequencing small molecule inhibitor targeted treatment therapeutic target therapy resistant transcriptome sequencing transcriptomics translational impact treatment response tumor tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT: Project 2 Outcomes for acute myeloid leukemia (AML) patients have improved little over four decades. This is largely due to the development of acquired drug resistance and refractory disease. Thus, there is an urgent need for new strategies to target residual AML cells or refractory clones before they trigger disease relapse. The tumor microenvironment is a key factor in the development of malignant progression and therapy resistance. The bi- directional communication between cancer cells and microenvironmental cells is much more complex than initially perceived. Thus, one strategy to reduce relapse is to target the signaling mediated by growth factors secreted by stromal or immune cells within the bone marrow microenvironment that play a critical role in promoting leukemia cell survival, development of drug resistance, and immune evasion. Therefore, the long- term goal of this project is to deconvolute the comprehensive network of events and cellular heterogeneity that contribute to acquired resistance in a context dependent manner to identify new therapeutic approaches. As part of our prior U54 DRSN funding, omics-based analysis of 350 primary AML patient samples found that multiple secreted cytokines and immune factors may contribute to drug resistance. Therefore, we hypothesize that reprogramming of the bone marrow niche modulates drug response and drives acquired resistance in AML. Comprehensive understanding of these mechanisms will lead to the identification of new combination therapies. We will focus on 5 essential therapeutic targets in AML: BCL2, FLT3, JAK2, MEK, and epigenetic pathways and will address this hypothesis following three well integrated aims. In Aim 1, we will map microenvironmental signatures and tumor cross-talk mechanisms against drug response features of AML by performing single cell gene expression and epigenetic analyses in the context of bone marrow niche. Tumor microenvironment cross- talk will be further explored in Aim 2 focusing on monocytes and stromal cells and in the context of NK and T cells in Aim 3 by performing CRISPR/Cas screening with co-culture platforms. Identified targets/pathways will be validated to fully define microenvironmental mechanisms of acquired drug resistance. These results will build predictive models of signaling crosstalk in response to therapeutic stress and identify combination therapies to overcome acquired resistance, particularly in the context of the microenvironment. We will test the effect of these inhibitors on cell viability, cellular heterogeneity, differentiation, and target inhibition using multi-parametric flow cytometry and immunofluorescence analysis. We will integrate these findings with Project 1 and prioritized targets will be tested for their translational impact in Project 3. Overall, elucidating the influence of microenvironment-driven signaling on drug response and survival of AML cells will help identify novel tractable targets for combination therapies to overcome acquired drug resistance in AML.

项目摘要/摘要：项目 2 四十多年来，急性髓系白血病 (AML) 患者的预后几乎没有改善。这很大程度上是由于获得性耐药性和难治性疾病的发展。因此，迫切需要新的在残留的 AML 细胞或难治性克隆引发疾病复发之前针对它们采取策略。肿瘤微环境是恶性进展和治疗耐药发生的关键因素。双癌细胞和微环境细胞之间的定向通讯比最初感知到的。因此，减少复发的一种策略是针对生长因子介导的信号传导由骨髓微环境中的基质细胞或免疫细胞分泌，在促进白血病细胞存活、耐药性的发展和免疫逃避。因此，长期该项目的长期目标是对事件和细胞异质性的综合网络进行解卷积有助于以依赖于环境的方式获得抵抗力，以确定新的治疗方法。作为一部分在我们之前的 U54 DRSN 资助中，对 350 个原发性 AML 患者样本进行基于组学的分析发现，多个分泌的细胞因子和免疫因子可能导致耐药性。因此，我们假设骨髓生态位的重新编程可调节药物反应并驱动 AML 的获得性耐药。对这些机制的全面了解将有助于确定新的联合疗法。我们将重点关注 AML 的 5 个重要治疗靶点：BCL2、FLT3、JAK2、MEK 和表观遗传通路将遵循三个综合目标来解决这一假设。在目标 1 中，我们将绘制微环境图通过执行单细胞研究针对 AML 药物反应特征的特征和肿瘤串扰机制骨髓生态位背景下的基因表达和表观遗传分析。肿瘤微环境交叉将在目标 2 中进一步探讨该话题，重点关注单核细胞和基质细胞以及 NK 和 T 通过使用共培养平台进行 CRISPR/Cas 筛选，对 Aim 3 中的细胞进行筛选。确定的目标/途径将进行验证以充分定义获得性耐药性的微环境机制。这些成果将建立响应治疗应激的信号串扰的预测模型并确定联合疗法克服获得性阻力，特别是在微环境中。我们将测试这些的效果使用多参数流抑制细胞活力、细胞异质性、分化和靶点抑制细胞计数和免疫荧光分析。我们将把这些发现与项目 1 结合起来并优先考虑目标将在项目 3 中测试其转化影响。总体而言，阐明了微环境驱动的药物反应和 AML 细胞存活信号将有助于识别新的易处理的药物联合疗法克服 AML 获得性耐药性的目标。