Impact of Leukemia Microenvironment on Response to Targeted Therapies in AML

急性髓细胞白血病（AML）患者的生存率<20%，30年来这一结果没有改变。 年这种令人沮丧的结果主要是由于耐药性和复发性疾病的发展。因此 目前迫切需要新的策略，在残余的AML细胞产生耐药性之前靶向它们。一种策略 减少复发的方法是靶向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 免疫逃避。我们的长期目标是确定新的药物靶点，以选择性地根除耐药 白血病克隆和克服耐药性，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小鼠存活的机制， 白血病细胞在94种细胞因子的离体筛选中，我们发现炎性细胞因子，如IL-1，HGF， MCP和FGF 2在不同的AML患者中升高，深刻影响AML患者的生存。 细胞这些残留的白血病细胞的存活和保护的增加最终导致药物治疗。 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）免疫反应受损的背景下， 白血病微环境这些结果提供了一个概念验证的例子， 微环境信号可以显著增强残留白血病细胞的有效靶向。以来 AML微环境极其复杂，我们预测各种其他炎性细胞因子和细胞因子可能与AML的微环境密切相关。 因子可以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AML微环境在药物治疗前后分泌的细胞因子进行全面分析， 骨髓基质基因表达特征和免疫细胞表征。我们将利用初级反洗钱 来自使用阿扎胞苷、FLT 3、BCL 2、JAK 2、PD-1和MEK抑制剂的正在进行的临床试验的样本。数据 将通过使用机器学习方法进行整合，并对优先路径进行验证， 确定它们在耐药性中的功能意义。我们将测试的假设，除了内在的 机制，微环境中存在的分泌和细胞因子有助于耐药性 和敏感性。表征这些外在途径将是至关重要的，以便开发更多的 增强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传导如何影响AML的药物反应和生存 细胞将有助于确定联合治疗的新的易处理的靶点。我们的研究也将适用于其他 依赖于这些炎症通路的癌症。

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.