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).

项目总结（最多30行）