Mechanisms of venetoclax combination activity in acute myeloid leukemia

维奈托克联合治疗急性髓系白血病的机制

• 批准号: 10416060
• 负责人: Stephen E Kurtz
• 金额: $ 34.52万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-02 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416060
• 关键词: Acute Myelocytic Leukemia; Automobile Driving; Azacitidine; BCL2 gene; Biological Markers; Biology; Blinded; CRISPR screen; Candidate Disease Gene; Cell Differentiation process; Cell Line; Cells; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Complex; Computer Models; Coupled; Data; Data Set; Dendritic Cells; Disease; Dropout; Drug Approval; Drug Combinations; Drug Targeting; Effectiveness; Elderly Acute Myeloblastic Leukemia; Enrollment; Enzymes; Evaluation; Event; Exhibits; FDA approved; FLT3 gene; Genes; Genetic; Genetic Transcription; Genomic approach; Goals; Hematologic Neoplasms; Immunophenotyping; Incentives; Laboratories; Mediating; Mediator of activation protein; Modeling; Mutate; Mutation; Myelogenous; Outcome; Pathway interactions; Patients; Pattern; Pharmacology; Population; Progression-Free Survivals; Proteomics; Refractory; Relapse; Research Personnel; Resistance; Sampling; Series; Signal Transduction; Specimen; Survival Rate; TP53 gene; Testing; Translating; Undifferentiated; Validation; Work; acute myeloid leukemia cell; base; biobank; biomarker validation; chemotherapy; clinical biomarkers; clinical predictors; clinical translation; clinical trial analysis; drug sensitivity; drug testing; functional genomics; genome-wide; genomic data; genomic platform; inhibitor; innovation; insight; knockout gene; macrophage; monocyte; neoplastic cell; novel; novel therapeutics; patient population; pre-clinical; predicting response; programs; prospective; resistance mechanism; response; response biomarker; screening; synergism; transcriptome sequencing; treatment strategy; tumor

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is one of the most common hematologic malignancies, representing a diverse collection of complex diseases. After 30-40 years without change of treatment strategy, the past 2 years have seen several drug approvals, including the most recent approval for the BCL2 inhibitor, venetoclax, used in combination with hypomethylating agents. While response rates of 60-80% with this combination are encouraging, the 1-year survival rate is still only at 30-40%. For the past decade, we have executed a functional genomics platform applied directly to primary samples from patients with AML and other hematologic malignancies. Using this platform, we have collectively studied over 2,500 primary patient specimens, and we have included a series of venetoclax combinations on this platform for the past five years. From this dataset, we have identified several novel venetoclax combinations with better activity than venetoclax plus hypomethylating agents, and we have started a clinical trial for one of the most promising of these combinations, venetoclax with the JAK inhibitor ruxolitinib. For this project, our long-term goals are to optimize and translate the most effective venetoclax drug combinations into the clinic for patients with AML. Our immediate goals are to understand the specific biology driving venetoclax combination synergy and identify biomarkers and mechanisms of response. Based on the central hypothesis that venetoclax combinations exhibit patterns and mechanisms of sensitivity and resistance that are specific to cell differentiation states and transcriptional programs. To accomplish these goals, 3 Aims are proposed: 1) Cell differentiation state as a mechanism of drug combination sensitivity and resistance – We will perform analytics of cell differentiation state in our large patient sample dataset as well as laboratory models of forced differentiation in cell lines and patient samples. 2) Synthetic lethality as a guide to mechanisms of drug combination sensitivity and resistance – Our preliminary data from genome-wide CRISPR/Cas screens point to specific candidate genes that impact on mediators of venetoclax combination activity. These candidates will be explored with genetic and pharmacologic perturbations. 3) Clinical validation of biomarkers and mechanisms of sensitivity and resistance – We have opened a clinical trial testing venetoclax combined with ruxolitinib in AML. We will have access to longitudinal specimens from patients on this trial. We will perform ex vivo drug testing on these trial specimens coupled with transcriptional and proteomic studies to evaluate the ability of each data type to predict clinical responses. Cumulatively, we expect these innovative analyses to have a major impact on our understanding of AML biology, with successful clinical translation of new, more effective drug combination strategies.

项目摘要/摘要 急性髓系白血病(AML)是最常见的血液系统恶性肿瘤之一，临床表现多样 复杂疾病的集合。在三四十年没有改变治疗策略之后，过去的两年 看到了几种药物的批准，包括最近批准的bcl2抑制剂ventoclax，用于 与低甲基化药物结合使用。而这种组合的响应率为60%-80% 令人鼓舞的是，一年存活率仍然只有30%-40%。在过去的十年里，我们执行了一项 功能基因组学平台直接应用于AML和其他血液病患者的原始样本 恶性肿瘤。利用这个平台，我们总共研究了2500多个初诊患者样本，我们 在过去的五年里，在这个平台上包括了一系列的ventoclax组合。从这个数据集中， 我们已经确定了几种比venotclax plus更具活性的新的ventoclax组合 去甲基化药物，我们已经开始了对其中一种最有希望的药物的临床试验 与JAK抑制剂ruxolitinib联合使用。对于这个项目，我们的长期目标是 优化和转化最有效的静脉滴注药物组合用于治疗慢性阻塞性肺疾病 AML。我们目前的目标是了解驱动文氏囊结合的特定生物学因素 协同作用，并确定生物标志物和反应机制。基于这样一个中心假设 百日咳的组合表现出敏感性和抗性的模式和机制 特定于细胞分化状态和转录程序。要实现这些目标，有三个目标 建议：1)细胞分化状态作为药物联合敏感性和耐药性的一种机制-我们将 在我们的大型患者样本数据集中执行细胞分化状态分析，以及 在细胞系和患者样本中强制分化。2)合成杀伤力作为药物作用机制的指南 联合敏感性和耐药性-我们来自全基因组CRISPR/CAS筛查的初步数据表明 影响文冠果结合活性介体的特定候选基因。这些候选人将成为 探索了遗传和药理学上的扰动。3)生物标志物和机制的临床验证 敏感性和耐药性-我们已经开始了一项临床试验，测试万乃馨与鲁索利替尼联合治疗 AML。在这项试验中，我们将获得患者的纵向标本。我们将进行体外药物治疗 对这些试验样本进行测试，结合转录和蛋白质组学研究，以评估 每种数据类型用于预测临床反应。总体而言，我们预计这些创新的分析将具有 主要影响我们对AML生物学的认识，随着临床的成功翻译新的、更有效的 药物组合策略。