Proteogenomic characterization of early and late resistance mechanisms in acute myeloid leukemia

项目概要/摘要 急性髓系白血病（AML）是最常见的血液恶性肿瘤之一，代表了多种类型的白血病。 复杂疾病的集合。在30 - 40年没有改变治疗策略后，过去2年 看到了几种药物的批准，包括最近批准的FLT3抑制剂，gilteritinib和BCL 2抑制剂， 维奈托克虽然对这两种药物的反应率令人鼓舞，但耐药性和复发仍然是一个问题。 对几乎所有的患者都有影响。在过去的十年里，我们已经执行了一个功能性蛋白质基因组学平台， 直接应用于AML和其他血液恶性肿瘤患者的原始样本。使用此 在这个平台上，我们已经共同研究了2,500多个主要患者标本。通过整合这些数据 利用广泛的蛋白质组学、磷酸化蛋白质组学、转录组学、基因组学、代谢组学、全基因组CRISPR 筛选和详细的临床注释，我们已经定义了生物标志物和反应机制 以及对FLT 3i和BCL 2i的早期和晚期抗性。因此，我们开始了临床试验， 可以减轻这些抗性机制的组合。对于这个项目，我们的长期目标是 翻译FLT3i和BCL 2i治疗方案，以便通过预先预防耐药性 组合和/或用序贯疗法减轻。我们的近期目标是定义和 优化对这些药物的反应和抗性的特定生物标志物。基于中心 AML总体蛋白质组学特征检测可作为药物反应预测因子的假设 并确定了耐药性发展过程中的动态变化， 洞察力，以产生新的，改进的药物组合。为了实现这些目标，临床前和临床 提出的工作：在早期和晚期抗性的细胞系模型上训练蛋白基因组学生物标志物-我们 我将对一组已衍生出耐药性的细胞系进行蛋白质基因组学分析 类似于耐药性的临床特征。验证存档患者样本材料中的签名-我们有 来自AML患者的标本的大量生物储存库，其中一个子集来自接受以下治疗的患者： FLT3i或BCL 2i作为标准治疗或作为我们正在进行的临床试验的一部分。我们将测试我们的细胞系 我们还将使用最先进的蛋白质组学技术， 使低输入材料能够研究分离的细胞群。敏感性生物标志物的临床验证 和耐药性-我们已经在AML中开展了测试FLT3i和BCL 2i组合的临床试验。我们会一起 从这些试验的患者中获得前瞻性纵向样本。我们将进行蛋白质基因组学 分析这些前瞻性样本，以评估我们的签名预测临床反应的能力。 累积起来，我们预计这些创新分析将对我们对AML生物学的理解产生重大影响， 新的、更有效的药物组合策略和预测性生物标志物的成功临床转化。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is one of the most common hematologic malignancies, representing a diverse collection of complex diseases. After 30-40 years without change of treatment strategy, the past 2 years have seen several drug approvals, including recent approvals for the FLT3 inhibitor, gilteritinib, and the BCL2 inhibitor, venetoclax. While response rates to both of these agents are encouraging, drug resistance and relapse is still problematic for nearly all patients. For the past decade, we have executed a functional proteogenomics platform applied directly to primary samples from patients with AML and other hematologic malignancies. Using this platform, we have collectively studied over 2,500 primary patient specimens. Through integration of these data with expansive proteomic, phospho-proteomic, transcriptomic, genomic, metabolomic, genome-wide CRISPR screens, and detailed clinical annotations, we have defined biomarkers and mechanisms underlying response as well as early and late resistance to both FLT3i and BCL2i. Consequently, we have started clinical trials testing combinations that may mitigate these resistance mechanisms. For this project, our long-term goals are to translate FLT3i and BCL2i therapeutic regimens such that resistance can be prevented with up-front combinations and/or mitigated with sequential therapies. Our immediate goals are to define and optimize specific biomarkers of response and resistance to these agents. Based on the central hypothesis that examination of global proteomic features of AML provides predictors of drug response and also identifies the dynamic changes during development of drug resistance, yielding mechanistic insight to generate novel, improved drug combinations. To accomplish these goals, Preclinical and Clinical work is proposed: Training of proteogenomic biomarkers on cell line models of early and late resistance – We will perform proteogenomic analyses of a panel of cell lines that have been derived to exhibit drug resistance resembling clinical features of resistance. Validation of signatures in archival patient sample material – We have a substantial biorepository of specimens from AML patients, a subset of which are from patients treated with FLT3i or BCL2i as standard-of-care or as part of our ongoing clinical trials. We will test our cell line derived biomarkers in these banked patient specimens, and we will also use cutting edge proteomics technology that enables low input material to study fractionated cell populations. Clinical validation of biomarkers of sensitivity and resistance – We have opened clinical trials testing FLT3i and BCL2i combinations in AML. We will have access to prospective, longitudinal specimens from patients on these trials. We will perform proteogenomic analyses on these prospective specimens to evaluate the ability of our signatures to predict clinical responses. Cumulatively, we expect these innovative analyses to have a major impact on our understanding of AML biology, with successful clinical translation of new, more effective drug combination strategies and predictive biomarkers.