Translating Improved Pairing and Timing of Drug Combination Strategies

项目概要：项目3 该项目的目标是将新发现的急性髓系白血病获得性耐药机制转化为 将项目1和2中的白血病（AML）转化为可以在疾病早期部署的新型药物组合 预防疾病复发和改善患者预后。AML的疾病复发是由 肿瘤细胞在骨髓微环境的支持下适应的复杂串扰。我们之前的工作， 由本项目的领导和人员与项目1和2密切合作进行， OHSU DRSN U 54（ARTNet的前身）的研究表明，AML中的获得性耐药性 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，并且这种早期抵抗最终过渡到具有以下特征的晚期抵抗阶段： 克隆进化理解这一过程为在治疗过程中进行干预创造了直接的转化机会。 抵抗的早期阶段。事实上，我们DRSN中心的工作已经导致了新的药物组合 已转化为临床，以减轻对AML重要新疗法（如FLT 3）的耐药性 和BCL 2抑制剂。这项先前的工作导致了一个中心假设，即描绘驱动路径 早期发现耐药性将导致改进药物组合的发展， 尽可能早地克服阻力，改善患者的预后。在这个项目中，我们 近期目标是优先考虑最有前途的药物组合和最可靠的耐药性 用于临床翻译的签名。为了实现这些目标，提出了三个目标：1）评估 在体外试验中使用原代AML样本的耐药性特征：我们将利用我们长期的专业知识 使用高通量筛查和药物组合检测原发性AML患者样本 平台，成像和基于流的读数，以评估单细胞中的表型效应，以及先进的3D 骨髓微环境模型，有助于对主要患者样本进行长期药物检测 （Humarrow）。2)接受合理治疗方案的患者样本的纵向评价：我们将 对我们最前沿的研究中招募的患者的纵向标本进行详细表征， 联合治疗临床试验，以评估治疗早期阶段的耐药性特征。3)采用 灵敏的检测技术，以检测初级样品中的低水平耐药性：我们将使用单细胞和 在新诊断和早期AML患者的标本中使用细胞富集分析技术， 可以检测到阻力特征的最早点。所有这些数据都将为工作提供信息和完善 项目1和项目2，并将用于支持未来临床试验的开发和临床- 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， 在尽可能早的阶段对患者进行治疗，从而防止疾病复发并改善持久的结果。

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.