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

• 批准号: 9444901
• 负责人: Anupriya Agarwal
• 金额: $ 72.78万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444901
• 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; 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; Impairment; Inflammatory; Interleukin-1; Intrinsic factor; JAK2 gene; Joints; MEKs; Machine Learning; Malignant Neoplasms; Marrow; Measures; Mediating; Modeling; Molecular Biology; Molecular Genetics; Monoclonal Antibodies; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Plasma; Play; Prevention; Proteins; Recombinant Proteins; Recurrent disease; Regulation; Relapse; Residual state; Resistance; Resistance development; Role; Sampling; Signal Transduction; Somatic Mutation; Source; Stromal Cells; Survival Rate; T-Lymphocyte; Testing; Transgenic Mice; Validation; Xenograft procedure; adaptive immune response; autocrine; cell growth; chemotherapy; combinatorial; cytokine; drug development; 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

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.

急性髓样白血病（AML）患者的存活率<20％，这一结果在30中没有改变 年。这种令人沮丧的结果在很大程度上是由于耐药性和复发性疾病的发展。因此，那里 迫切需要在产生抗性之前靶向残留AML细胞的新策略。一种策略 减少复发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，耐药性的发展中起关键作用， 和免疫逃避。我们的长期目标是确定新颖的药物靶标，以选择性地消除耐药性 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，我们发现炎性细胞因子，例如IL-1，HGF， 在多种AML患者中升高的MCP和FGF2对AML的生存产生了深远的影响 细胞。这些残留白血病细胞的生存和保护最终导致药物 电阻和靶向这些生存途径可以克服抗药性。除了抵抗 有针对性的治疗，我们还拥有数据，以表明免疫微环境参与免疫逃避。 具体而言，我们的数据表明自适应（T细胞）免疫反应在 白血病微环境。这些结果提供了概念验证的示例 微环境信号可能会显着增强残留白血病细胞的有效靶向。自从 AML微环境非常复杂，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 分泌细胞因子的AML微环境前后药物治疗的全面分析， 骨髓基因基因表达特征和免疫细胞表征。我们将利用主要AML 使用Azacitidine，FLT3，BCL2，JAK2，PD-1和MEK抑制剂的临床试验中的样本。数据 获得的将通过使用机器学习方法进行集成，优先级的途径将被验证为 确定它们在耐药性中的功能意义。我们将测试以下假设：除了固有 机理，微环境中存在的分泌和细胞因子有助于耐药性 和AML的灵敏度。这些外在途径的表征至关重要 有效的组合疗法，以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AML的药物反应和存活率 细胞将有助于鉴定新的可用于联合疗法的可拖动靶标。我们的研究也适用于其他 依赖这些炎症途径的癌症。