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） 我们开发了一项研究人员发射的临床试验，以测试组合或ruxolitinib和venetoclax （RUX+VEN）基于广泛的离体小分子的救济/难治性AML患者（NCT03874052） 从数百个主要AML样品中收集的抑制剂筛选数据。初步试验结果表明 单个周期后，在某些患者中获得的缓解可容忍良好的组合。我们的合作 与戴维斯博士的提案将利用来自试验患者的骨髓和外周血样本 用每种单一药物和药物组合以及质量分辨率处理的离体和药物组合 细胞仪（细胞仪）。虽然Cytof可以解决在肿瘤内异质性，以进行药物筛查的水平 单个单元格，未解决所需的复杂数据所需的分析。利用优势 plevritis博士小组开发了一种新型算法的细胞和解决分析方法的需求 （药物nem）分析单个白血病细胞的单细胞，单毒的扰动反应 确定针对个别患者的优化药物组合策略。细胞分析将检查AML 表型，JAK-STAT信号，BCL2家族蛋白和细胞代谢的单个细胞上的细胞代谢 接受研究治疗的患者。我们假设通过使用药物NEM，我们可以预测对组合的反应 基于对单药治疗的体外反应的处理。我们将比较我们对 患者的实际反应并确定与组合抗性有关的细胞特征。到 确定抗药性的潜在机制，我们将对收集的患者样品进行细胞因子阿萨斯 通过治疗。我们假设从微环境发出的细胞因子信号可以发挥 在用RUX+VEN治疗的患者中耐药性中的关键作用。如果药物NEM预测准确，它将 提供概念证明，用于使用单人药物数据为组合疗法提供信息，从而提供更多 有效且实用的方法来研究未来的组合治疗。如果发现特定的细胞因子 有助于RUX+VEN电阻，可以阐明克服电阻的方法。总体而言，我们的 拟议的补充项目利用我们的联合优势来预测药物反应并进一步预测 了解AML患者耐药性的机制。此申请正在提交请求 耐药性和敏感性中心（DRSC）的补充预算以执行 卡拉·戴维斯（Kara Davis）博士的行政补充申请书中提出的合作工作标题为 “使用质量解剖AML中新型联合疗法的单细胞反应或抗性 响应于非CA-21-034的细胞仪”“特殊兴趣通知（NOSI）：行政 补充剂以支持与NCI支持的耐药性和敏感性的合作 网络（DRSN）。