Impact of Leukemia Microenvironment on Response to Targeted Therapies in AML

白血病微环境对 AML 靶向治疗反应的影响

基本信息

批准号：
9985234
负责人：
Anupriya Agarwal
金额：
$ 45.08万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9985234
关键词：
Acute Myelocytic Leukemia Address Affect Aftercare Automobile Driving Azacitidine BCL2 gene Biological Assay Bone Marrow Bone marrow biopsy Cell Survival Cell physiology Cells Cellular Assay Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Combined Modality Therapy Complex Computer Simulation Cytokine Receptors Data Drug Combinations Drug resistance Epigenetic Process Evaluation FGF2 gene FLT3 gene FLT3 inhibitor Future Gene Expression Profile Genetic Techniques Genetic Transcription Goals Growth Factor Immune Immune Evasion Immune response Immune system Immunohistochemistry Immunosuppression Immunotherapy Impairment Inflammatory Interleukin-1 Intrinsic factor JAK2 gene Joints Leukemic Cell MEKs Machine Learning Malignant Neoplasms Marrow Measures Mediating Modeling Molecular Biology Molecular Genetics Monoclonal Antibodies Outcome PD-1 inhibitors Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Plasma Play Prevention Proteins Recombinant Proteins Recurrent disease Regulation Relapse Residual state Resistance Resistance development Role SLEB2 gene Sampling Signal Transduction Somatic Mutation Source Stromal Cells Survival Rate T-Lymphocyte Testing Transgenic Mice Validation Xenograft procedure acute myeloid leukemia cell adaptive immune response anti-tumor immune response autocrine cell growth chemotherapy combinatorial cytokine drug development drug relapse drug sensitivity experimental study immune checkpoint immune checkpoint blockade improved in vivo inhibitor/antagonist kinase inhibitor leukemia mouse model new therapeutic target novel paracrine response small hairpin RNA small molecule targeted agent targeted treatment therapeutic target transcriptomics tumor

项目摘要

The survival rate of acute myeloid leukemia (AML) patients is <20%, an outcome that has not changed in 30 years. This dismal outcome is largely due to development of drug resistance and relapsed disease. Thus, there is an urgent need for new strategies to target residual AML cells before they develop resistance. One strategy to reduce relapse is to target the secreted cytokines, growth factors, and immune cells within the bone marrow microenvironment that play a critical role in promoting leukemia cell survival, development of drug resistance, and immune evasion. Our long-term goal is to identify novel drug targets to selectively eradicate resistant leukemic clones and overcome drug resistance to improve the future treatment of AML patients. To do this, we have begun to identify the mechanisms by which the bone marrow microenvironment promotes survival of leukemia cells. In an ex vivo screen of 94 cytokines, we found that inflammatory cytokines, such as IL-1, HGF, MCPs, and FGF2, which are elevated in a diverse set of AML patients, profoundly affects the survival of AML cells. The increased survival and protection of these residual leukemia cells eventually leads to drug resistance, and targeting these survival pathways can overcome resistance. In addition to resistance to targeted therapy, we also have data to suggest the immune microenvironment is involved in immune evasion. Specifically, our data suggest that adaptive (T cell) immune responses are impaired in the context of the leukemia microenvironment. These results provided a proof-of-concept example in which targeting microenvironmental signals may significantly enhance effective targeting of residual leukemia cells. Since the AML microenvironment is extremely complex, we predict that various other inflammatory cytokines and cellular factors may modulate response to targeted therapy. Therefore, in the proposed study we will perform comprehensive profiling of the AML microenvironment pre and post drug treatment for secreted cytokines, marrow stromal gene expression signature, and immune cell characterization. We will leverage primary AML samples from ongoing clinical trials using Azacitidine, FLT3, BCL2, JAK2, PD-1 and MEK inhibitors. The data obtained will be integrated by using machine-learning approaches and prioritized pathways will be validated to identify their functional significance in drug resistance. We will test the hypothesis that in addition to intrinsic mechanisms, the secreted and cellular factors present in the microenvironment contribute to drug resistance and sensitivity in AML. Characterizing these extrinsic pathways will be critical in order to develop more effective combination therapies that enhance drug sensitivity and overcome resistance. Relevance: Elucidating how microenvironment-driven signaling influence drug response and survival of AML cells will help identify novel tractable targets for combination therapy. Our study will also be applicable to other cancers that are dependent on these inflammatory pathways.

急性髓系白血病 (AML) 患者的生存率<20%，这一结果在 30 年来都没有改变年。这种令人沮丧的结果主要是由于耐药性和疾病复发的发展。因此，有迫切需要新的策略在残留的 AML 细胞产生耐药性之前对其进行靶向治疗。一个策略减少复发的方法是针对骨髓内分泌的细胞因子、生长因子和免疫细胞微环境在促进白血病细胞存活、耐药性发展中发挥关键作用，和免疫逃避。我们的长期目标是确定新的药物靶点以选择性根除耐药性白血病克隆并克服耐药性，以改善 AML 患者的未来治疗。为此，我们已经开始确定骨髓微环境促进存活的机制白血病细胞。在 94 种细胞因子的离体筛选中，我们发现炎症细胞因子，如 IL-1、HGF、 MCP 和 FGF2 在不同的 AML 患者中升高，深刻影响 AML 的生存细胞。这些残留白血病细胞的存活率和保护力的提高最终导致药物的出现抵抗力，并针对这些生存途径可以克服抵抗力。除了抵抗靶向治疗中，我们还有数据表明免疫微环境参与免疫逃避。具体来说，我们的数据表明适应性（T 细胞）免疫反应在白血病微环境。这些结果提供了一个概念验证示例，其中目标微环境信号可以显着增强对残留白血病细胞的有效靶向。自从 AML微环境极其复杂，我们预测各种其他炎症细胞因子和细胞因素可能会调节对靶向治疗的反应。因此，在拟议的研究中，我们将执行对分泌细胞因子药物治疗前后的 AML 微环境进行全面分析，骨髓基质基因表达特征和免疫细胞特征。我们将利用初级反洗钱来自正在进行的使用阿扎胞苷、FLT3、BCL2、JAK2、PD-1 和 MEK 抑制剂的临床试验的样本。数据获得的信息将通过使用机器学习方法进行整合，并且优先路径将被验证确定它们在耐药性中的功能意义。我们将检验以下假设：除了内在的机制，微环境中存在的分泌因子和细胞因子有助于耐药性和 AML 的敏感性。为了开发更多的外在途径，表征这些外在途径至关重要有效的联合疗法可增强药物敏感性并克服耐药性。相关性：阐明微环境驱动的信号传导如何影响药物反应和 AML 的生存细胞将有助于确定联合治疗的新的易处理靶标。我们的研究也将适用于其他依赖于这些炎症途径的癌症。