Architecture and Trajectory of Acquired Resistance to Therapy in AML

项目总结：总体 该计划的长期目标是确定急性髓系获得性耐药的机制 白血病(AML)，从而可以部署新的药物组合来防止疾病复发和改善患者状况 结果。AML的总体五年存活率保持在20%，这一结果几年来没有改变 几十年。尽管近年来已经批准了七种新的治疗急性髓系白血病的方案，但改进的初始方案 这些疗法的缓解率不会带来持久的结果。疾病复发是由一种复杂的 肿瘤细胞在骨髓微环境的支持下适应的串扰。这起案件的调查人员 建议的Artnet中心已经合作了15年以上，包括作为DRSN财团的中心- Artnet的前身。我们之前的工作包括开发迄今为止最大的功能基因组 AML患者样本数据集、全基因组CRISPR筛查、AML与基质相互作用的广泛研究 和免疫细胞，以及不同药物组合的测试。这些研究导致了&gt；150的合作 出版物，15年以上的持续合作资金，创建大量大型数据集存放到 公共资料库，并将研究结果转化为大量临床试验。我们最重要的假设是 获得性耐药性的结构受时间、外在和内在因素的支配， 阐明这一轨迹将有助于确定适当的治疗策略以延缓 摆脱获得性抵抗，并保持在肿瘤进化和适应的领先地位。这一假设将得到检验。 通过三个综合良好的项目解决以下问题：1)AML肿瘤细胞是如何 生物适应于逃避治疗压力？我们将使用全基因组CRISPR平台以及长期 原发AML患者样本的祖细胞扩增以了解反馈途径和转移表观遗传学 以及可能导致获得性耐药性的细胞状态。2)间质和免疫是如何 微环境控制耐药性？我们将使用共培养和先进的骨髓模型来执行 全基因组筛选和测试单一药物对急性髓系白血病微环境串扰的影响。穿过 计算模型，我们将提名靶向策略来缓解肿瘤外部耐药信号和 增强免疫抗肿瘤反应。3)耐药性特征和药物组合如何才能有效 临床翻译？我们将使用高通量和先进的人类骨髓工程模型来 测试项目1和项目2中目标药物的组合并确定其优先顺序。我们还将研究纵向样本 来自参加正在进行的临床试验的患者。所有这些数据将为项目1和项目1的工作提供信息并加以改进 2.我们的中心将由一个管理核心和一个功能表型核心提供支持。总体而言，我们 将全面了解急性髓系白血病获得性耐药性，并确定新的治疗方案 尽早治疗患者，防止复发，实现持久缓解。

PROJECT SUMMARY: Overall The long-term goal of this Program is to define mechanisms of acquired drug resistance in acute myeloid leukemia (AML) so that novel drug combinations can be deployed to prevent disease relapse and improve patient outcomes. The overall five-year survival rate for AML remains 20%, an outcome that has not changed for several decades. Although seven new regimens have been approved for AML in recent years, the improved initial remission rates with these therapies do not lead to durable outcomes. Disease relapse is fueled by a complex cross-talk of tumor cells adapting with support from the bone marrow microenvironment. The investigators of this proposed ARTNet Center have collaborated for 15+ years, including as a Center in the DRSN consortium – the predecessor to ARTNet. Our prior work has involved development of the largest-to-date functional genomic dataset on AML patient samples, genome-wide CRISPR screens, broad studies of AML interactions with stromal and immune cells, and testing of diverse drug combinations. These studies have led to >150 collaborative publications, continuous collaborative funding for 15+ years, creation of numerous large datasets deposited into public repositories, and translation of findings into numerous clinical trials. Our overarching hypothesis is that the architecture of acquired drug resistance is governed by temporal extrinsic and intrinsic factors and elucidating this trajectory will allow for the identification of properly timed therapeutic strategies to stave off acquired resistance and stay ahead of tumor evolution and adaptation. This hypothesis will be tested through three well integrated Projects addressing the following questions: 1) How does AML tumor cell intrinsic biology adapt to evade therapeutic pressure? We will use genome-wide CRISPR platforms as well as long-term progenitor expansion of primary AML patient samples to understand feedback pathways and shifting epigenetic and cell state landscapes that can drive acquired drug resistance. 2) How does the stromal and immune microenvironment govern drug resistance? We will use co-culture and advanced bone marrow models to perform genome-wide screens and test the impact of single-agents on AML-microenvironment cross-talk. Through computational modeling, we will nominate targeting strategies to mitigate tumor extrinsic resistance signals and boost immune anti-tumor responses. 3) How can resistance signatures and drug combinations be effectively clinically translated? We will use high-throughput and advanced, engineered models of human bone marrow to test and prioritize drug combinations from targets in Projects 1 and 2. We will also study longitudinal specimens from patients enrolled on ongoing clinical trials. All of these data will inform and refine the work of Projects 1 and 2. Our Center will be supported by an Administrative Core and a Functional Phenotyping Core. Collectively, we will develop a comprehensive understanding of acquired drug resistance in AML and identify new regimens to treat patients at the earliest possible stage, prevent relapse, and achieve durable remissions.