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.

项目总结：项目3 该项目的目标是将新发现的急性髓系获得性耐药机制 白血病(AML)从项目1和项目2转化为可在疾病早期部署的新型药物组合 为防止疾病复发和改善患者预后而进行的进化。急性髓系白血病的疾病复发是由 在骨髓微环境的支持下，肿瘤细胞适应的复杂串扰。我们之前的工作， 这是由本项目的领导和人员与项目1和项目2密切合作进行的 OHSU DRSN U54--Artnet的前身--的研究表明，在急性髓系白血病中获得耐药性 通过一个多阶段的过程进行。早期的耐药性是由肿瘤刺激的细胞状态变化驱动的- 外在信号，这种早期的抗性最终过渡到具有以下特征的后期抗性 克隆进化。了解这一过程可立即提供翻译机会，以便在 抵抗的早期阶段。事实上，我们在DRSN中心的工作已经导致了新的药物组合 已经转化为临床，以减轻对重要的急性髓细胞白血病新疗法的耐药性，如Flt3 和bcl2抑制剂。这项先前的工作导致了一个中心假设，即描述驾驶路径 及早发现抗药性将导致改进药物组合的发展，在 尽可能早的时间，以克服阻力，改善患者的预后。对于这个项目，我们的 眼下的目标是优先考虑最有希望的药物组合和最可靠的耐药性 临床翻译的签名。为了实现这些目标，本文提出了三个目标：1)评估 在体外检测中使用原始AML样本的耐药性特征：我们将利用我们长期的专业知识 使用两种高通量筛查来检测初级AML患者样本与药物组合的关系 平台、成像和基于流动的读数来评估单细胞的表型效应，以及先进的3D 促进初级患者样本长期药物测试的骨髓微环境模型 (Humrow)。2)对接受合理治疗方案的患者的样本进行纵向评估：我们将 对来自我们尖端技术的患者的纵向标本进行详细的表征 联合治疗临床试验，以评估治疗早期阶段的耐药性特征。3)员工 在初级样本中检测低水平耐药性的敏感检测技术：我们将使用单细胞和 新诊断和早期AML患者标本中的细胞浓缩分析技术 可以检测到耐药性特征的最早时间点。所有这些数据都将提供信息并改进工作 项目1和2，并将被用来支持未来临床试验的发展和临床- 获得性耐药性的信息性签名。总的来说，这项工作将确定新的治疗方案 使患者尽早接受治疗，从而防止疾病复发和改善持久结果。