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: 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
• 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

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)患者的存活率为20%，这一结果在30年内没有改变。 好几年了。这一令人沮丧的结果在很大程度上是由于耐药性的产生和疾病的复发。因此，在那里 迫切需要新的策略，在残留的AML细胞产生耐药性之前将其作为靶点。一种策略 减少复发就是针对骨髓中分泌的细胞因子、生长因子和免疫细胞。 微环境在促进白血病细胞存活、耐药发展方面发挥关键作用， 和免疫逃避。我们的长期目标是寻找新的药物靶点，选择性地根除耐药性 白血病克隆和克服耐药性，以改善未来AML患者的治疗。为了做到这一点，我们 已经开始确定骨髓微环境促进白血病存活的机制 白血病细胞。在94种细胞因子的体外筛选中，我们发现炎性细胞因子，如IL-1，HGF， MCPS和FGF2在一组不同的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和保护作用的增强最终导致了药物的出现 抗药性，而针对这些生存途径可以克服耐药性。除了抵抗 靶向治疗，我们也有数据表明免疫微环境参与了免疫逃避。 具体地说，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的例子，在这个例子中 微环境信号可显著增强残留白血病细胞的有效靶向。自.以来 AML的微环境极其复杂，我们预测其他各种炎性细胞因子和细胞 各种因素可能会调节对靶向治疗的反应。因此，在拟议的研究中，我们将进行 对急性髓系白血病分泌细胞因子治疗前后微环境的综合分析， 骨髓基质基因表达特征，免疫细胞特性。我们将利用主要的AML 来自正在进行的使用氮胞苷、Flt3、BCL2、JAK2、PD-1和MEK抑制剂的临床试验的样本。数据 将使用机器学习方法集成所获得的信息，并将验证优先路径 确定它们在耐药中的功能意义。我们将检验这一假设，除了内在的 微环境中存在的分泌和细胞因子导致耐药性的机制 急性髓系白血病的敏感性。确定这些外在途径的特征对于开发更多的 提高药物敏感性和克服耐药性的有效联合疗法。 相关性：阐明微环境驱动的信号转导如何影响AML的药物反应和生存 细胞将有助于为联合疗法识别新的易处理的靶点。我们的研究也将适用于其他 依赖于这些炎症途径的癌症。