Translating Improved Pairing and Timing of Drug Combination Strategies

转化药物组合策略的改进配对和时机

• 批准号: 10684113
• 负责人: BRIAN J DRUKER
• 金额: $ 30.41万
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684113
• 关键词: 3-Dimensional; ATAC-seq; Acute Myelocytic Leukemia; Architecture; Automobile Driving; BCL2 gene; Biological Assay; Biological Markers; Blood Vessels; Bone Marrow; Cell Communication; Cell Differentiation process; Cell Line; Cell model; Cells; Clinical; Clinical Trials; Clonal Evolution; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Complex; Correlative Study; Data; Detection; Development; Disease; Drug Combinations; Drug resistance; Early Diagnosis; Epigenetic Process; Evaluation; Evolution; FLT3 gene; Flow Cytometry; Future; Gene Expression; Goals; Human; Human Resources; Image; Immune; Immunosuppression; Immunotherapy; Institution; Intervention; Leukemic Cell; Measures; Metabolic; Methodology; Methods; Modeling; Mutation; Natural Killer Cells; Newly Diagnosed; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Process; Proteins; Recurrent disease; Regimen; Relapse; Research Personnel; Resistance; Resistance development; Sampling; Signal Transduction; Specimen; Stromal Cells; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Therapy Clinical Trials; Time; Transcript; Translating; Translations; Validation; Work; acquired drug resistance; acute myeloid leukemia cell; bone engineering; clinical translation; deep sequencing; detection method; drug testing; high throughput screening; improved; inhibitor; leukemia; longitudinal analysis; metabolomics; mutational status; neoplastic cell; novel; novel drug combination; novel therapeutics; operation; participant enrollment; predictive signature; prevent; resistance mechanism; resistance mutation; response; single cell analysis; single-cell RNA sequencing; small molecule; targeted treatment; therapy resistant; three-dimensional modeling; translational potential; tumor

PROJECT SUMMARY: Project 3 The goal of this Project is to translate newly discovered mechanisms of acquired drug resistance in acute myeloid leukemia (AML) from Projects 1 and 2 into novel drug combinations that can be deployed early in disease evolution to prevent disease relapse and improve patient outcomes. Disease relapse in AML is fueled by a complex cross-talk of tumor cells adapting with support from the bone marrow microenvironment. Our prior work, which was conducted by Leads and Personnel in this Project collaborating closely with Projects 1 and 2 as part of the OHSU DRSN U54 – the predecessor to ARTNet – has shown that acquired drug resistance in AML proceeds via a multi-stage process. Early resistance is driven by cell state changes stimulated from tumor- extrinsic signals, and this early resistance eventually transitions to a late stage of resistance with features of clonal evolution. Understanding this process creates immediate translational opportunities for intervention during the early stage of resistance. Indeed, our work from the DRSN Center has already led to novel drug combinations that have been translated into clinical to mitigate resistance to important new therapies for AML, such as FLT3 and BCL2 inhibitors. This prior work has led to a central hypothesis that delineation of pathways driving early detection of drug resistance will lead to the development of improved drug combinations, at the earliest time possible, to overcome resistance and improve patient outcomes. For this project, our immediate goals are to prioritize the most promising drug combinations and most reliable resistance signatures for clinical translation. To accomplish these goals, three Aims are proposed: 1) Evaluate signatures of resistance using primary AML samples in ex vivo assays: We will use our long-standing expertise of testing primary AML patient samples against drug combinations using both high-throughput screening platforms, imaging and flow-based readouts to evaluate phenotypic effects in single-cells, and an advanced, 3D model of the bone marrow microenvironment that facilitates long-term drug testing of primary patient samples (Humarrow). 2) Longitudinal evaluation of samples from patients receiving rational therapeutic regimens: We will perform detailed characterization of longitudinal specimens from patients enrolled on our cutting-edge combination therapy clinical trials to evaluate signatures of resistance at early stages of therapy. 3) Employ sensitive detection techniques to detect low levels of resistance in primary samples: We will use single-cell and cell enrichment analytical techniques in specimens from newly diagnosed and early-stage AML patients to define the earliest point at which resistance signatures can be detected. All of these data will inform and refine the work of Projects 1 and 2 and will be leveraged to support the development of future clinical trials and clinically- informative signatures of acquired drug resistance. Collectively, this work will identify new regimens to treat patients at the earliest possible stage, thereby, preventing disease relapse and improving durable outcomes.

项目摘要：项目3 该项目的目的是翻译急性髓样中获得的耐药性的新发现的机制 项目1和2的白血病（AML）进入新型药物组合，可以在疾病早期部署 进化以防止疾病缓解并改善患者的预后。 AML中的疾病缓解是由 肿瘤细胞的复杂串扰在骨髓微环境的支持下适应。我们先前的工作， 该项目中的潜在客户和人员进行了与项目1和2紧密合作的一部分 ARTNET的前身OHSU DRSN U54的of已表明AML获得了耐药性 通过多阶段过程进行。早期抗性是由肿瘤刺激的细胞状态变化驱动的 外在信号，这种早期抵抗最终转变为阻力的后期，特征的特征 克隆进化。了解这一过程会为干预的立即转化机会 抵抗的早期阶段。确实，我们来自DRSN中心的工作已经导致了新颖的毒品组合 已转化为临床，以减轻对AML重要新疗法的抵抗力，例如FLT3 和BCL2抑制剂。这项先前的工作导致了一个中心假设，即驱动途径的描述 早期检测耐药性将导致改善药物组合的发展 最早可能的时间，以克服抵抗力并改善患者的预后。对于这个项目，我们的 直接的目标是优先考虑最有希望的药物组合和最可靠的抵抗 临床翻译的特征。为了实现这些目标，提出了三个目标：1）评估 使用主要AML样品在离体测定中使用电阻的签名：我们将使用长期的专业知识 使用高通量筛选测试针对药物组合的初级AML患者样品的测试 平台，成像和基于流动的读数，以评估单细胞中的表型效应以及高级3D 骨髓微环境的模型，可促进原代患者样品的长期药物测试 （Humarrow）。 2）对接受合理治疗方案的患者的样本的纵向评估：我们将 对入学的患者进行纵向标本的详细表征 联合治疗临床试验，以评估治疗早期抗药性的特征。 3）雇用 敏感检测技术以检测主要样本中低水平的抗性：我们将使用单细胞和 来自新诊断和早期AML患者的样品中的细胞富集分析技术以定义 可以检测到电阻特征的最早点。所有这些数据都将告知和完善工作 在项目1和2的项目中，并将利用以支持未来临床试验的发展和临床 获得性耐药性的信息签名。总的来说，这项工作将确定用于治疗的新方案 因此，患者最早可能阶段，从而防止疾病缓解并改善耐用结果。