Dissecting Single-cell Response or resistance to novel combination therapy in AML using mass cytometry

使用质谱流式细胞仪剖析单细胞对 AML 新型联合疗法的反应或耐药

• 批准号: 10411840
• 负责人: BRIAN J DRUKER
• 金额: $ 9.33万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411840
• 关键词: Achievement; Acute Myelocytic Leukemia; Address; Administrative Supplement; Adult; Algorithms; Azacitidine; BCL2 gene; Biological Assay; Biology; Blood specimen; Bone Marrow; Budgets; Cell Line; Cells; Clinical; Clinical Distribution; Clinical Trials; Clonal Expansion; Collaborations; Combined Modality Therapy; Correlative Study; Cytokine Signaling; Cytometry; Data; Decitabine; Disease; Disease remission; Drug Combinations; Drug Screening; Drug resistance; Drug usage; Elderly; Enrollment; Exhibits; FDA approved; Future; Gene Family; Genes; Goals; In Vitro; Individual; Laboratories; Leukemic Cell; Light; Marrow; Metabolism; Modeling; Mutation; Myelogenous; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Plasma; Play; Protein Family; Refractory; Relapse; Research; Research Personnel; Resistance; Resolution; Sampling; Signal Transduction; Specimen; TP53 gene; Technology; Testing; Work; acute myeloid leukemia cell; base; cancer therapy; clinical application; clinical biomarkers; clinical sequencing; cohort; complex data; cytokine; drug response prediction; drug sensitivity; functional genomics; improved; individual patient; inhibitor/antagonist; insight; interest; kinase inhibitor; leukemia; novel; novel drug combination; novel marker; patient response; peripheral blood; predicting response; progenitor; programs; prospective; relapse patients; resistance mechanism; response; response biomarker; sample collection; screening; single cell analysis; small molecule inhibitor; synergism; tumor heterogeneity

Project Summary (max 30 lines) We developed an investigator-initiated clinical trial to test the combination or ruxolitinib and venetoclax (Rux+Ven) in relapse/refractory AML patients (NCT03874052) based upon extensive ex vivo small molecule inhibitor screening data collected from hundreds of primary AML samples. Preliminary trial results show the combination is well tolerated with remissions obtained in some patients after a single cycle. Our collaborative proposal with Dr. Davis will make use of marrow and peripheral blood samples from trial patients that have been treated ex vivo with each single agent and the drug combination along with single-cell resolution of mass cytometry (CyTOF). While CyTOF can address intratumoral heterogeneity for drug screening at the level of the single cell, the required analytics for the resulting complex data were not addressed. Leveraging the strengths of CyTOF and addressing the need for analysis approaches, Dr. Plevritis’ group developed a novel algorithm (DRUG-NEM) that analyzes single-cell, single-drug perturbation responses on individual leukemia cells to identify optimized drug combination strategies for individual patients. The CyTOF analysis will examine AML phenotype, JAK-STAT signaling, BCL2 family proteins and cellular metabolism on individual cells from the patients treated on study. We hypothesize that by using DRUG-NEM we can predict response to combination treatment based on in vitro response to single agent treatment. We will compare our predicted response to the patient’s actual response and determine cellular features associated with resistance to the combination. To identify potential mechanisms of resistance we will perform cytokine assays on patient samples collected throughout treatment. We hypothesize that cytokine signals emanating from the microenvironment could play a key role in drug resistance in patients treated with Rux+Ven. If the DRUG-NEM predictions are accurate, it will provide proof of concept for using single-agent drug data to inform combination therapy, thus, providing a more efficient and practical approach to study future combination treatments. If specific cytokines are found to contribute to Rux+Ven resistance, approaches to overcome the resistance can be elucidated. Overall, our proposed supplement project makes use of our combined strengths to predict drug response and further understand mechanisms of drug resistance in AML patients. This application is being submitted to request a supplemental budget for the Drug Resistance and Sensitivity Center (DRSC) to perform the collaborative work as proposed in Dr. Kara Davis’ administrative supplement application titled "Dissecting Single-Cell Response or Resistance to Novel Combination Therapy in AML Using Mass Cytometry ” in response to NOT-CA-21-034 “Notice of Special Interest (NOSI): Administrative Supplements to Support Collaborations with the NCI-supported Drug Resistance and Sensitivity Network (DRSN).

项目摘要（最多30行） 我们开展了一项药物启动的临床试验，以测试ruxolitinib和venetoclax的组合 (Rux+Ven），基于广泛的离体小分子 从数百个原发性AML样本中收集的抑制剂筛选数据。初步试验结果显示， 联合用药耐受性良好，一些患者在单周期后获得缓解。我们的协作 戴维斯博士的一项提案将使用来自试验患者的骨髓和外周血样本， 用每种单一药剂和药物组合沿着离体处理， 流式细胞术（CyTOF）。虽然CyTOF可以解决肿瘤内异质性，用于在肿瘤水平上进行药物筛选， 在单个单元格中，没有解决所产生的复杂数据的所需分析。利用优势 为了解决对分析方法的需求，Plevelman博士的研究小组开发了一种新的算法， （DRUG-NEM），其分析单个白血病细胞上的单细胞、单药物扰动响应， 为个体患者确定优化的药物组合策略。CyTOF分析将检查AML 表型，JAK-STAT信号传导，BCL 2家族蛋白和细胞代谢对个体细胞的影响。 研究中接受治疗的患者。我们假设，通过使用药物-NEM，我们可以预测联合治疗的反应， 基于对单一药剂治疗的体外反应的治疗。我们将比较我们的预测反应， 患者的实际反应并确定与对组合的抗性相关的细胞特征。到 确定潜在的耐药机制我们将对收集的患者样本进行细胞因子测定 在整个治疗过程中。我们假设，从微环境中发出的细胞因子信号可能在细胞内起作用。 在Rux+Ven治疗患者的耐药性中起关键作用。如果药物NEM预测准确， 为使用单药药物数据为联合治疗提供信息提供概念证明，从而提供更多 有效和实用的方法来研究未来的联合治疗。如果发现特定的细胞因子 有助于Rux+Ven抗性，可以阐明克服抗性的方法。总体而言，我们 拟议的补充项目利用我们的综合优势来预测药物反应，并进一步 了解AML患者的耐药机制。本申请是为了请求 耐药性和敏感性中心（DRSC）执行 卡拉·戴维斯博士的行政补充申请中提出的合作工作， “使用质谱分析AML中对新型联合疗法的单细胞反应或抗性 细胞计数“，以响应NOT-CA-21-034“特别关注通知（NOSI）：管理 支持与NCI支持的耐药性和敏感性研究合作的补充材料 网络（DRSN）。