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: 10629248
• 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/10629248
• 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; Enzymes; Evaluation; Event; Exhibits; FDA approved; FLT3 gene; Genes; Genetic; Genetic Transcription; Genomic approach; Goals; Hematologic Neoplasms; Immunophenotyping; Incentives; Laboratories; Macrophage; Mediating; Mediator; Modeling; Mutate; Mutation; Myelogenous; Outcome; Pathway interactions; Patients; Pattern; 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; biobank; biomarker identification; biomarker validation; chemotherapy; clinical biomarkers; clinical predictors; clinical translation; clinical trial analysis; drug sensitivity; drug testing; functional genomics; genome-wide; genomic data; genomic platform; improved; inhibitor; innovation; insight; knockout gene; monocyte; myeloid leukemia cell; neoplastic cell; novel; novel therapeutics; participant enrollment; patient population; pharmacologic; 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.

项目总结/摘要 急性髓系白血病（AML）是最常见的血液恶性肿瘤之一，代表了多种类型的白血病。 复杂疾病的集合。在30-40年没有改变治疗策略后，过去2年 看到了几种药物的批准，包括最近批准的BCL 2抑制剂venetoclax，用于 与低甲基化剂组合。虽然这种组合的反应率为60-80%， 令人鼓舞的是，一年生存率仍然只有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。使用这个平台，我们已经共同研究了2,500多个原始患者标本， 在过去的五年里，在这个平台上包括了一系列的venetoclax组合。从这个数据集来看， 我们已经鉴定了几种新的维奈托克组合，其活性优于维奈托克+， 低甲基化剂，我们已经开始了一项临床试验，其中最有希望的一种 维奈托克与JAK抑制剂鲁索利替尼的组合。对于这个项目，我们的长期目标是 优化并将最有效的维奈托克药物组合转化为临床， 急性髓细胞白血病我们的近期目标是了解驱动venetoclax组合的特定生物学 协同作用和鉴定生物标志物和反应机制。基于中心假设， 维奈托克组合显示出敏感性和抗性的模式和机制， 特异于细胞分化状态和转录程序。为了实现这些目标，有三个目标： 提出：1）细胞分化状态作为药物组合敏感性和抗性的机制-我们将 在我们的大型患者样本数据集以及实验室模型中分析细胞分化状态， 在细胞系和患者样品中强制分化。2)综合致死率作为药物作用机制的指南 组合敏感性和抗性-我们来自全基因组CRISPR/Cas筛选的初步数据表明， 影响维奈托克组合活性介质的特定候选基因。这些候选人将在 基因和药理学上的干扰。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， 急性髓细胞白血病我们将获得本试验患者的纵向样本。我们将进行体外药物 对这些试验标本进行检测，并结合转录和蛋白质组学研究，以评估 每种数据类型来预测临床反应。累积起来，我们预计这些创新分析将有一个 对我们对AML生物学的理解产生重大影响，成功地将新的、更有效的药物转化为临床药物 联合用药策略。