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: 10517762
• 负责人: BRIAN J DRUKER
• 金额: $ 36.96万
• 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/10517762
• 关键词: Acute Myelocytic Leukemia; Architecture; Automobile Driving; BCL2 gene; Biological Assay; Bone Marrow; Cells; Clinical; Clinical Trials; Clonal Evolution; Combined Modality Therapy; Complex; Data; Development; Disease; Drug Combinations; Drug resistance; Early Diagnosis; Enrollment; Evaluation; Evolution; FLT3 gene; Future; Goals; Human Resources; Image; Intervention; Newly Diagnosed; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Process; Recurrent disease; Regimen; Resistance; Sampling; Signal Transduction; Specimen; Techniques; Testing; Therapeutic; Therapy Clinical Trials; Time; Translating; Work; acquired drug resistance; base; clinical translation; detection method; drug testing; high throughput screening; improved; inhibitor; neoplastic cell; novel drug combination; novel therapeutics; prevent; therapy resistant; three-dimensional modeling; 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 该项目的目标是将新发现的急性髓系获得性耐药机制转化为 项目 1 和 2 中的白血病 (AML) 转化为可在疾病早期部署的新型药物组合 进化以防止疾病复发并改善患者的治疗结果。 AML 疾病复发的原因是 肿瘤细胞在骨髓微环境的支持下进行适应的复杂串扰。我们之前的工作， 作为项目 1 和 2 的一部分，该项目的领导和人员与项目 1 和 2 密切合作进行 OHSU DRSN U54（ARTNet 的前身）的研究表明，AML 中获得性耐药 通过多阶段过程进行。早期抵抗是由肿瘤刺激的细胞状态变化驱动的 外在信号，这种早期抵抗最终过渡到晚期抵抗，其特征为 克隆进化。理解这个过程可以为干预创造直接转化机会 抵抗初期。事实上，我们 DRSN 中心的工作已经带来了新的药物组合 已转化为临床以减轻对 AML 重要新疗法（例如 FLT3）的耐药性 和 BCL2 抑制剂。这项先前的工作得出了一个中心假设，即驱动路径的描绘 早期检测耐药性将导致改进药物组合的开发 尽早克服阻力并改善患者的治疗效果。对于这个项目，我们的 近期目标是优先考虑最有希望的药物组合和最可靠的耐药性 临床翻译签名。为了实现这些目标，提出了三个目标： 1) 评估 在离体检测中使用主要 AML 样本进行耐药性特征：我们将利用我们长期积累的专业知识 使用高通量筛选测试原发性 AML 患者样本与药物组合的对比 平台、成像和基于流的读数来评估单细胞的表型效应，以及先进的 3D 骨髓微环境模型有利于对主要患者样本进行长期药物测试 （胡马罗）。 2）对接受合理治疗方案的患者样本进行纵向评价：我们将 对我们尖端技术上登记的患者的纵向标本进行详细表征 联合治疗临床试验评估治疗早期阶段的耐药特征。 3）雇用 灵敏的检测技术来检测初级样品中的低水平耐药性：我们将使用单细胞和 对新诊断和早期 AML 患者的标本进行细胞富集分析技术来定义 可以检测到电阻特征的最早点。所有这些数据将为工作提供信息并完善工作 项目 1 和 2 的成果将用于支持未来临床试验和临床的开发 获得性耐药性的信息特征。总的来说，这项工作将确定新的治疗方案 尽早让患者接受治疗，从而防止疾病复发并改善持久结果。