Architecture and Trajectory of Acquired Resistance to Therapy in AML

项目总结：总体 该项目的长期目标是确定急性髓系白血病患者获得性耐药的机制。 从而可以部署新药物组合以防止疾病复发并改善患者的 结果。AML的总体五年生存率仍为20%，这一结果在几年内没有改变。 几十年尽管近年来已经批准了七种新的AML治疗方案，但改进的初始治疗方案仍然存在。 这些疗法的缓解率不会导致持久的结果。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。这件事的调查人员 拟议的ARTNet中心已经合作了15年以上，包括作为DRSN联盟的中心- ARTNet的前身。我们先前的工作涉及到迄今为止最大的功能基因组的发展， AML患者样本数据集，全基因组CRISPR筛选，AML与基质相互作用的广泛研究 和免疫细胞，以及测试不同的药物组合。这些研究导致了150多个合作项目。 出版物，持续合作资助15年以上，创建大量大型数据集，存入 公共知识库，并将研究结果转化为众多临床试验。我们的首要假设是 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， 摆脱获得性耐药性，并领先于肿瘤的进化和适应。这一假设将得到检验 通过三个很好的综合项目解决以下问题：1）AML肿瘤细胞如何内在 生物学适应逃避治疗压力？我们将使用全基因组CRISPR平台以及长期 原代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 和细胞状态的景观，可以驱动获得性耐药性。2)基质和免疫系统是如何 微环境决定耐药性？我们将使用共培养和先进的骨髓模型来进行 全基因组筛选和测试单一药物对AML微环境串扰的影响。通过 计算模型，我们将提名靶向策略，以减轻肿瘤外源性耐药信号， 增强免疫抗肿瘤反应。3)耐药性特征和药物组合如何有效地 临床翻译？我们将使用高通量和先进的人类骨髓工程模型， 测试并优先考虑项目1和2中目标的药物组合。我们还将研究纵向标本 来自正在进行的临床试验的患者。所有这些数据都将为项目1和项目2的工作提供信息和改进， 2.我们的中心将由一个行政核心和一个功能表型核心支持。我们共同 将全面了解AML的获得性耐药性，并确定新的治疗方案， 在尽可能早的阶段治疗患者，防止复发，并实现持久缓解。

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.