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 AML 中单细胞对新型联合疗法的反应或耐药性

基本信息

批准号：
10383056
负责人：
Kara Lynn Davis
金额：
$ 14.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383056
关键词：
Acute Myelocytic Leukemia Address Algorithms Antineoplastic Agents BCL2 gene BRAF gene Bone Marrow Cell Death Cells Cellular Metabolic Process Clinical Clinical Trials Collaborations Combination Drug Therapy Combined Modality Therapy Cytometry DNA Sequence Alteration Data Development Diagnosis Diagnostic Disease Disease remission Drug Combinations Drug Screening Drug resistance Drug usage ERBB2 gene Enrollment Epidermal Growth Factor Receptor Family member Future Genetic Genetic Heterogeneity Hematopoietic Neoplasms Heterogeneity Hour In Vitro Individual Learning Leukemic Cell Link MEKs Metabolic Metabolism Modeling Mutation Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Protein Family Refractory Relapse Research Personnel Resistance Resolution Role Sampling Signal Transduction Specimen Testing Tyrosine Kinase Inhibitor base clinical predictors combat complex data drug response prediction drug sensitivity high dimensionality individual patient inhibitor/antagonist interest leukemia malignant breast neoplasm melanoma mutant non-genetic novel novel drug combination novel therapeutics older patient pre-clinical predicting response response screening single cell analysis single cell technology small molecule targeted agent targeted treatment tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-21-034. Acute myeloid leukemia (AML) is among the deadliest blood cancers with over 10,000 patients dying annually in the U.S. AML displays notorious genetic heterogeneity with thousands of mutations described across AML patient tumors to date. AML has benefited from the rise of targeted therapies although clinical impact of individual targeted agents has been modest. In AML, impressive initial response rates of 60- 80% have been observed in elderly patients using the combination of venetoclax, a BCL2 inhibitor, and hypomethylating agents. Yet, survival at one year is only 30-40%, suggesting more to learn about the efficacy of this combination. Novel ex vivo drug screening platforms have identified additional venetoclax combinations. In particular, venetoclax with ruxolitinib, a JAK tyrosine kinase inhibitor, is a promising combination therapy. Based on this preclinical data, a novel clinical trial has been initiated for patients with relapsed or refractory AML. Cancer drug combination decisions are primarily made on the basis of mutational heterogeneity, yet evidence of non-genetic drug resistance among isogenic cells is mounting, particularly with single cell analysis. Despite advances in single cell technologies, there are currently no strategies for making drug combination decisions that utilize single cell platforms to explicitly address intratumoral heterogeneity. Leveraging the strengths of CyTOF and addressing the need for analysis approaches, we 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 the individual patient. Using mass cytometry analysis with focus on AML phenotype, signaling and metabolism, we will determine ex vivo response to single agent venetoclax or ruxolitinib or the combination. Using the single agent treatment data, we will use DRUG-NEM to predict response to the combination and compare to patient samples obtained on trial after staring combination therapy. If predictions are accurate, it provides proof of concept for using single-agent drug data to inform combination therapy, thus a more efficient and practical approach to study future combination treatments and will inform sensitivity or resistance to venetoclax in combination with ruxolitinib in patients with AML.

项目概要本申请是为了响应特殊利益通知（NOSI）而提交的，该通知被确定为不是-CA-21-034。急性髓系白血病 (AML) 是最致命的血液癌症之一，有超过 10,000 例美国每年都有 AML 患者死亡，这些患者表现出臭名昭著的遗传异质性，其中有数千种突变迄今为止，已在 AML 患者肿瘤中得到描述。尽管 AML 受益于靶向治疗的兴起个别靶向药物的临床影响不大。在 AML 中，令人印象深刻的初始响应率为 60- 80% 的老年患者在使用 Venetoclax（一种 BCL2 抑制剂）和低甲基化剂。然而，一年的生存率仅为 30-40%，这表明需要更多地了解其疗效这个组合。新型离体药物筛选平台已鉴定出其他维奈托克组合。特别是，venetoclax 与 JAK 酪氨酸激酶抑制剂 ruxolitinib 是一种有前途的联合疗法。基于这一临床前数据，针对复发或难治性癌症患者启动了一项新的临床试验。反洗钱。癌症药物组合决策主要是根据突变异质性做出的，然而同基因细胞之间非遗传耐药性的证据越来越多，特别是通过单细胞分析。尽管单细胞技术取得了进步，但目前尚无药物组合的策略利用单细胞平台明确解决瘤内异质性的决策。利用结合 CyTOF 的优势并满足分析方法的需求，我们开发了一种新颖的算法（DRUG-NEM）分析单个白血病细胞的单细胞、单一药物扰动反应确定针对个体患者的优化药物组合策略。使用质谱流式分析重点关注 AML 表型、信号传导和代谢，我们将确定对单一药物的体外反应维奈托克或鲁索替尼或组合。利用单药治疗数据，我们将使用 DRUG-NEM 来预测对组合的反应并与开始组合后试验中获得的患者样本进行比较治疗。如果预测准确，它可以为使用单药药物数据提供信息提供概念证明联合治疗，因此是研究未来联合治疗的更有效和实用的方法将告知 AML 患者对维奈托克与鲁索替尼联合用药的敏感性或耐药性。