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

急性髓系白血病早期和晚期耐药机制的蛋白质组学特征

• 批准号: 10646375
• 负责人: BRIAN J DRUKER
• 金额: $ 114.47万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646375
• 关键词: Acute Myelocytic Leukemia; Archives; Automobile Driving; Azacitidine; BCL2 gene; Biological Assay; Biological Markers; Biological Process; Biology; CD14 gene; CD34 gene; CRISPR screen; Cell Differentiation process; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Collection; Complex; Data; Decitabine; Dependence; Development; Disease; Disease remission; Drug Approval; Drug Combinations; Drug Modelings; Drug resistance; Early Diagnosis; Elderly Acute Myeloblastic Leukemia; Exhibits; Exposure to; FLT3 gene; FLT3 inhibitor; Generations; Genes; Genetic; Genomics; Goals; Hematologic Neoplasms; MEKs; Metabolic; Metabolism; Methods; Modeling; Mutation; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphoproteins; Population; Proteins; Proteomics; Publishing; Regimen; Relapse; Residual Neoplasm; Resistance; Role; Sampling; Signal Transduction; Specimen; Stromal Cells; Technology; Testing; Training; Translating; Validation; Work; acquired drug resistance; arm; aurora B kinase; biobank; biomarker validation; cell type; chemotherapy; clinical material; clinical predictors; clinical translation; clinical trial enrollment; data integration; drug relapse; drug resistance development; drug response prediction; drug sensitivity; genome-wide; improved; inhibitor; inhibitor therapy; innovation; insight; leukemia; metabolomics; monocyte; novel; novel drug combination; novel strategies; novel therapeutics; participant enrollment; phosphoproteomics; pre-clinical; pre-clinical research; predictive marker; predictive panel; prevent; progenitor; prospective; proteogenomics; resistance mechanism; response; response biomarker; specific biomarkers; standard of care; therapy resistant; transcriptomics; treatment strategy; tumor; tumor microenvironment

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.

项目摘要/摘要 急性髓样白血病（AML）是最常见的血液系统恶性肿瘤之一，代表潜水员 复杂疾病的收集。 30 - 40年后，没有改变治疗策略，过去2年有 请参阅几个药物批准，包括最近对FLT3抑制剂的批准，Gilteritinib和Bcl2抑制剂， Venetoclax。虽然对这两个代理人的回应率令人鼓舞，但耐药性和缓解仍在 几乎所有患者都有问题。在过去的十年中，我们执行了功能性蛋白质组学平台 直接应用于AML和其他血液学恶性肿瘤患者的主要样品。使用此 平台，我们共同研究了2500多个主要患者标本。通过集成这些数据 具有额外的蛋白质组学，磷酸蛋白质组，转录组，基因组，代谢组，全基因组CRISPR 屏幕和详细的临床注释，我们确定了生物标志物和机制 以及对FLT3I和BCL2I的早期和晚期抵抗。因此，我们已经开始临床试验测试 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BCL2I治疗方案，以便可以预防阻力 结合和/或通过顺序疗法缓解。我们的直接目标是定义和 优化对这些药物的反应和抗性的特定生物标志物。基于中央 假设AML的全球蛋白质组学特征的检查提供了药物反应的预测指标 还可以确定在耐药性开发过程中的动态变化，并产生机理 洞察力产生新颖的，改进的药物组合。为了实现这些目标，临床前和临床 提出了工作：在早期和晚期耐药性细胞系模型上培训蛋白质组生物标志物 - 我们 将对已得出暴露耐药性的一系列细胞系进行蛋白质原理分析 类似于阻力的临床特征。验证存档患者样本材料中的签名 - 我们有 来自AML患者的标本的实质性生物剂，其中一部分来自接受治疗的患者 作为护理标准或作为我们正在进行的临床试验的一部分，FLT3I或BCL2I。我们将测试我们的细胞系 这些存放的患者标本中的生物标志物，我们还将使用尖端蛋白质组学技术 使低输入材料能够研究分离的细胞群体。灵敏度生物标志物的临床验证 和抗性 - 我们已经打开了AML中的flt3i和BCL2I组合的临床试验。我们将有 从这些试验中获取患者的前瞻性纵向标本。我们将执行蛋白质组学 对这些前瞻性标本进行分析，以评估我们的签名预测临床反应的能力。 累积地，我们希望这些创新的分析对我们对AML生物学的理解有重大影响， 随着新的，更有效的药物组合策略和预测生物标志物的成功临床翻译。

项目成果

Oncoproteomic profiling of AML: moving beyond genomics.

• DOI: 10.1080/14789450.2023.2176757
• 发表时间: 2022-07
• 期刊: EXPERT REVIEW OF PROTEOMICS
• 影响因子: 3.4
• 作者: Joshi, Sunil K.;Tognon, Cristina E.;Druker, Brian J.;Rodland, Karin D.
• 通讯作者: Rodland, Karin D.

Decomprolute is a benchmarking platform designed for multiomics-based tumor deconvolution.

Decomprute 是一个基准测试平台，专为基于多组学的肿瘤反卷积而设计。

• DOI: 10.1016/j.crmeth.2024.100708
• 发表时间: 2024
• 期刊: Cell reports methods
• 作者: Feng,Song;Calinawan,Anna;Pugliese,Pietro;Wang,Pei;Ceccarelli,Michele;Petralia,Francesca;Gosline,SaraJC
• 通讯作者: Gosline,SaraJC