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
基本信息
- 批准号:10411840
- 负责人:
- 金额:$ 9.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AchievementAcute Myelocytic LeukemiaAddressAdministrative SupplementAdultAlgorithmsAzacitidineBCL2 geneBiological AssayBiologyBlood specimenBone MarrowBudgetsCell LineCellsClinicalClinical DistributionClinical TrialsClonal ExpansionCollaborationsCombined Modality TherapyCorrelative StudyCytokine SignalingCytometryDataDecitabineDiseaseDisease remissionDrug CombinationsDrug ScreeningDrug resistanceDrug usageElderlyEnrollmentExhibitsFDA approvedFutureGene FamilyGenesGoalsIn VitroIndividualLaboratoriesLeukemic CellLightMarrowMetabolismModelingMutationMyelogenousPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhosphotransferasesPlasmaPlayProtein FamilyRefractoryRelapseResearchResearch PersonnelResistanceResolutionSamplingSignal TransductionSpecimenTP53 geneTechnologyTestingWorkacute myeloid leukemia cellbasecancer therapyclinical applicationclinical biomarkersclinical sequencingcohortcomplex datacytokinedrug response predictiondrug sensitivityfunctional genomicsimprovedindividual patientinhibitor/antagonistinsightinterestkinase inhibitorleukemianovelnovel drug combinationnovel markerpatient responseperipheral bloodpredicting responseprogenitorprogramsprospectiverelapse patientsresistance mechanismresponseresponse biomarkersample collectionscreeningsingle cell analysissmall molecule inhibitorsynergismtumor heterogeneity
项目摘要
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)
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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{{ truncateString('BRIAN J DRUKER', 18)}}的其他基金
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:
10460000 - 财政年份:2022
- 资助金额:
$ 9.33万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 9.33万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
9788295 - 财政年份:2018
- 资助金额:
$ 9.33万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
10003014 - 财政年份:2018
- 资助金额:
$ 9.33万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
10605266 - 财政年份:2018
- 资助金额:
$ 9.33万 - 项目类别:
Knight Scholars Program - Building STEM Interest and Capacity for Cancer Research Careers among Underrepresented and Rural High School Students
奈特学者计划 - 培养代表性不足和农村高中生癌症研究职业的 STEM 兴趣和能力
- 批准号:
10381451 - 财政年份:2018
- 资助金额:
$ 9.33万 - 项目类别:
Functional Genomic Discovery of Pathway Targeted and Immune Modulatory Therapeutic Combinations in Hematologic Malignancies
血液系统恶性肿瘤中通路靶向和免疫调节治疗组合的功能基因组发现
- 批准号:
10238859 - 财政年份:2017
- 资助金额:
$ 9.33万 - 项目类别:
Translating Improved Pairing and Timing of Drug Combination Strategies
转化药物组合策略的改进配对和时机
- 批准号:
10684113 - 财政年份:2017
- 资助金额:
$ 9.33万 - 项目类别:
Architecture and Trajectory of Acquired Resistance to Therapy in AML
AML 获得性治疗耐药的结构和轨迹
- 批准号:
10684101 - 财政年份:2017
- 资助金额:
$ 9.33万 - 项目类别:
Translating Improved Pairing and Timing of Drug Combination Strategies
转化药物组合策略的改进配对和时机
- 批准号:
10517762 - 财政年份:2017
- 资助金额:
$ 9.33万 - 项目类别:
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