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

驱动 AML 药物组合疗效和耐药性的肿瘤内在和微环境机制

• 批准号: 10012768
• 负责人: BRIAN J DRUKER
• 金额: $ 115.5万
• 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/10012768
• 关键词: Acute Myelocytic Leukemia; Automobile Driving; BCL2 gene; Back; Biological Assay; Biology; Bone Marrow; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Collection; Combined Modality Therapy; Complex; Computer Analysis; Data; Data Set; Development; Diagnostic; Disease; Drug Combinations; Drug Kinetics; Drug resistance; Environment; Evaluation; Event; Exposure to; FLT3 gene; Future; Gene Targeting; Genes; Genetic; Goals; Hematologic Neoplasms; Immune; Immunocompetent; Immunophenotyping; Immunosuppression; Inflammatory; Knowledge; Lesion; Light; MEKs; Malignant Neoplasms; Modeling; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Plasma; Population; Research Personnel; Resistance; Resolution; Sampling; Signal Pathway; Signal Transduction; Stromal Cells; T-Lymphocyte; Testing; Therapeutic; Translating; Validation; Vision; Work; Xenograft procedure; acute myeloid leukemia cell; base; candidate validation; cell growth; clinical investigation; clinical translation; cohort; combinatorial; cytokine; drug candidate; drug sensitivity; drug testing; effective therapy; exome; experimental study; functional genomics; genome-wide; genomic data; genomic profiles; immune checkpoint; improved; improved outcome; in vivo; in vivo evaluation; innovation; leukemia; mortality; mouse model; neoplastic cell; novel; novel drug combination; novel strategies; personalized medicine; pre-clinical; programs; prospective; resistance mechanism; response; small molecule; standard of care; targeted agent; targeted treatment; therapy outcome; therapy resistant; transcriptome sequencing; treatment strategy; tumor

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.

项目概要-总体 急性髓系白血病（AML）是最常见的血液恶性肿瘤之一，代表了多种类型的白血病。 复杂疾病的集合。AML的治疗策略在30-40年内没有改变。单药 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， 最好该DRSC项目的研究人员，规避耐药性的药物组合（D2CR）， 合作了十多年，并开发了用于评估原发性AML的功能性基因组管道。 这些患者样本共同导致了许多具有诊断和治疗意义的发现。 对于这个项目，我们的长期目标是将有效的靶向肿瘤的药物组合转化为 内在和微环境途径进入临床AML患者。我们的近期目标 优先考虑每种AML最相关的肿瘤内在和微环境途径 疾病子集，并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。基于中心假设，靶向肿瘤内在的药物组合 AML生物学的外在特征对于开发更有效和 持久的治疗策略，我们预测，这种D2CR-DRSC建立的药物组合， 该计划将大大改善AML患者的预后。为了实现这些目标，3 提出了以下研究课题：1）影响药物敏感性的肿瘤内在基因和途径是什么 和抵抗？将对亲本和耐药AML细胞进行全基因组CRISPR/Cas筛选， 与世界上最大的功能性基因组AML队列的计算分析相结合。结果将 提名基因/途径，用于在基因编辑模型中对患者样本进行验证，并用于药物组合 研究项目3。2)促进肿瘤细胞生长、耐药性、 和免疫抑制我们的大型AML患者样本库的炎性细胞因子谱将在 进行。我们的AML患者骨髓基质细胞库也将用于研究反应性 这些基质细胞暴露于特定药物时的特征。最后，高参数免疫分型 和T细胞功能测定将用于确定免疫景观与候选药物测试中， 免疫活性的自发性AML小鼠模型。候选目标将被提名进行组合 肿瘤内在靶点的研究。3)哪些药物组合最有效地桥接肿瘤- 内在和微环境生物学消除AML细胞和规避耐药性？药物组合 将对原代AML患者样本进行离体检测， 使用AML患者来源的异种移植物。累积起来，我们预计这些创新分析将产生重大影响。 影响我们对AML生物学的理解，成功地临床转化为新的、更有效的药物 组合策略。