Tumor Intrinsic and Microenvironmental Mechanisms Driving Drug Combination Efficacy and Resistance in AML

项目总结--总体 急性髓系白血病(AML)是最常见的血液系统恶性肿瘤之一，临床表现多样 复杂疾病的集合。AML的治疗策略在30-40年内没有改变。单代理 基于AML遗传学或微环境疾病特征的靶向治疗一直令人失望，在 最好的。这项名为D2CR的药物组合项目的研究人员已经 合作了十多年，并开发了用于评估原发AML的功能基因组管道 患者样本共同导致了许多具有诊断和治疗意义的发现。 对于这项计划，我们的长期目标是转化针对肿瘤的有效药物组合- AML患者进入临床的内在和微环境途径。我们的近期目标 是为每个AML确定最相关的肿瘤内在和微环境途径 疾病亚组和建立足够的临床前数据，以促进立即进行临床研究 药物组合。基于以下中心假设：针对肿瘤的药物组合是内在的 而AML生物学的外在特征将是发展更有效和 持久的治疗策略，我们预测由D2CR-DrSc建立的药物组合 该计划将大大改善急性髓细胞白血病患者的预后。为实现这些目标，3 项目被提出：1)哪些肿瘤内在基因和途径对药物敏感性有贡献？ 那抵抗呢？对亲本和耐药AML细胞进行全基因组CRISPR/CAS筛查将是 与世界上最大的功能基因组急性髓系白血病队列的计算分析相结合。结果将是 提名用于在基因编辑模型和药物组合中对患者样本进行验证的基因/途径 项目3.2中的研究)促进肿瘤细胞生长、耐药性、 免疫抑制呢？我们的大量AML患者样本的炎性细胞因子分析将是 指挥。我们的急性髓系白血病患者骨髓基质细胞库也将被用于反应性研究。 这些间质细胞在接触特定药物时的特征。最后，高参数免疫表型 T细胞功能分析将被用来定义免疫格局，候选药物将在 具有免疫功能的自发性急性髓系白血病小鼠模型。候选目标将被提名进行组合 关于肿瘤内在靶点的研究。3)哪些药物组合最有效地连接肿瘤- 消除AML细胞和规避耐药性的内在和微环境生物学？药物组合 来自项目1和2中提名的靶点将在原发AML患者样本上进行体外测试和体内测试 使用AML患者来源的异种移植物。总体而言，我们预计这些创新分析将有一个主要的 随着新的、更有效的药物的成功临床翻译，对我们对AML生物学的理解产生了影响 组合策略。

PROJECT SUMMARY – Overall Acute myeloid leukemia (AML) is one of the most common hematologic malignancies, representing a diverse collection of complex diseases. Treatment strategies for AML have not changed in 30-40 years. Single-agent targeted therapies based on AML genetics or microenvironmental disease features have been disappointing, at best. The investigators on this DRSC Program, Drug Combinations to Circumvent Resistance (D2CR), have collaborated for over a decade and have developed functional genomic pipelines for evaluation of primary AML patient samples that have collectively led to numerous discoveries with diagnostic and therapeutic implications. For this Program, our long-term goals are to translate effective drug combinations that target tumor- intrinsic and microenvironmental pathways into the clinic for patients with AML. Our immediate goals are to prioritize the most relevant tumor-intrinsic and microenvironmental pathways for each AML disease subset and establish sufficient preclinical data to facilitate immediate clinical investigation of drug combinations. Based on the central hypothesis that drug combinations targeting tumor intrinsic and extrinsic features of AML biology will be essential to the development of more effective and durable therapeutic strategies, we predict that the drug combinations established by this D2CR-DRSC Program will substantially improve outcomes for patients with AML. To accomplish these goals, 3 Projects are proposed: 1) What are the tumor-intrinsic genes and pathways that contribute to drug sensitivity and resistance? Genome-wide CRISPR/Cas screens on parental and drug-resistant AML cells will be integrated with computational analysis of the largest functional genomic AML cohort in the world. The result will nominate genes/pathways for validation on patient samples in gene-edited models and for drug combination studies in Project 3. 2) What are the tumor-extrinsic pathways promoting tumor cell growth, drug resistance, and immune suppression? Inflammatory cytokine profiling of our large bank of AML patient samples will be conducted. Our bank of AML patient bone marrow stromal cells will also be accessed for studies of the reactive signature of these stromal cells when exposed to specific drugs. Finally, high-parameter immunophenotyping and T-cell functional assays will be used to define the immune landscape with candidate drugs tested in an immune-competent, spontaneous mouse model of AML. Candidate targets will be nominated for combination studies with tumor-intrinsic targets. 3) What are the drug combinations that most effectively bridge tumor- intrinsic and microenvironmental biology to eliminate AML cells and circumvent resistance? Drug combinations from targets nominated in Project 1 and 2 will be tested ex vivo on primary AML patient samples and in vivo using AML patient-derived xenografts. Cumulatively, we expect these innovative analyses to have a major impact on our understanding of AML biology, with successful clinical translation of new, more effective drug combination strategies.