New Therapeutic Vulnerabilities for Aggressive B-Cell Lymphoma

侵袭性 B 细胞淋巴瘤的新治疗漏洞

• 批准号: 10653834
• 负责人: John L. Cleveland
• 金额: $ 54.36万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653834
• 关键词: Apoptosis; Apoptotic; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; BCL1 Oncogene; BCL2 gene; Biology; Bone Marrow; C-terminal; Cancer Cell Growth; Cell Cycle Progression; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular Metabolic Process; ChIP-seq; Chemicals; Chromosomal Duplication; Chromosomal translocation; Clinical; Clinical Trials; Coin; Combined Modality Therapy; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Data; Disease; Drug Combinations; Drug Screening; Drug Targeting; Drug resistance; Enhancers; Foundations; Gene Expression; Genes; Genetic Transcription; Genomics; Growth; Histologic; Laboratories; Leucine Zippers; Lymphoma; Lymphoma cell; Maintenance; Malignant Neoplasms; Metabolism; Modeling; Molecular; Mus; Oncogenes; Oncogenic; Oncoproteins; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacotherapy; Phenotype; Phosphorylation; Phosphotransferases; Protein Kinase; Proteomics; Publishing; RNA Polymerase II; Refractory; Research; Resistance; Resistance development; Role; Sampling; Signal Transduction; Specimen; Testing; Therapeutic; Transcription Elongation; Treatment Efficacy; Tumorigenicity; Up-Regulation; bropirimine; cell growth; chemotherapy; cofactor; data integration; effective therapy; in vivo; inhibitor; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; pharmacologic; pre-clinical; programs; response; screening; targeted treatment; therapeutic evaluation; therapy resistant; tool; transcription factor; transcriptome; transcriptome sequencing; transcriptomic profiling; treatment response; tumor microenvironment; uncontrolled cell growth

Project Summary Double-hit lymphoma (DHL) and double-expressing lymphoma (DEL) are aggressive subtypes of diffuse large B cell lymphoma (DLBCL) that are characterized by translocations or amplifications of both MYC and BCL2 oncogenes, or that co-overexpress MYC and BCL2 oncoproteins, respectively. MYC and BCL2 drive cancer cell growth and metabolism, or confer a marked resistance to apoptosis, respectively. Accordingly, patients with DHL or DEL respond poorly to chemotherapy and targeted therapies, and currently lack effective treatment options; indeed DHL and DEL are currently considered incurable. Thus, there is an urgent need to define new therapeutically tractable vulnerabilities for the treatment of DHL and DEL. Recently, we modeled DHL using a platform that includes bone marrow stroma and that mimics the DHL tumor microenvironment. Using this platform we implemented unbiased activity-based proteomic profiling, drug screens, RNA-seq and ChIP-seq studies to identify essential pathways and targets that are manifest in DHL. Quite strikingly, these analyses revealed that DHL have a unique super-enhancer (SE) landscape, where SE manifest in DHL are associated with genes that control the lymphoma cell fate or oncogenic signaling. Further, these screens revealed that DHL and DEL cell lines and primary patient specimens are highly sensitive to inhibitors of the general transcription apparatus. In particular, all DHL and DEL cells are exquisitely sensitive to THZ1, a newly identified covalent inhibitor of cyclin- dependent kinase 7 (CDK7) that functions as a transcriptional co-factor and that phosphorylates the C-terminal domain of RNA polymerase-II. Furthermore, our studies with a selective inhibitor of CDK9 coined NVP2 revealed that DHL and DEL cells survival also requires the activity of this kinase, which regulates transcriptional elongation. Notably our new findings have established that both CDK7 and CDK90 function are essential to maintain MYC expression in models of DHL and DEL. We hypothesize that MYC-, CDK7- and CDK9- dependent transcription and BCL-2 overexpression cooperatively drive the aggressive phenotypes of DHL and DEL and, accordingly, that combined inhibition of CDK7 or CDK9 and BCL-2 triggers synthetic lethality in these aggressive lymphomas. Using our cell-based platform, DHL and DEL cell line models, DHL patient-derived xenografts (PDX) and a syngeneic mouse DHL model that are available in our laboratories, our respective expertise, and our unique access to large numbers of primary DHL patient specimens, we will address the role of CDK7 and CDK9 in the maintenance of DHL, and we will define the mechanism by which CDK7/CDK9 sustains the expression of oncogenic drivers in this lethal malignancy. Finally, we will strategically target the transcriptional machinery and pre-clinically validate a therapeutic strategy that combines drugs that disable CDK7, CDK9 and BCL2 as a synthetic therapeutic approach to treat DHL and DEL. !

项目摘要 双重淋巴瘤（DHL）和双表达淋巴瘤（DEL）是侵略性的亚型 B细胞淋巴瘤（DLBCL）以MYC和BCL2的易位或扩增为特征 Oncogenes或该共表达MYC和BCL2癌蛋白分别。 MYC和BCL2驱动癌细胞 生长和代谢，或分别赋予对凋亡的明显抗性。因此，DHL患者 或DEL对化学疗法和靶向疗法的反应不佳，目前缺乏有效的治疗选择； 确实，DHL和DEL目前被认为是无法治愈的。因此，迫切需要定义新的 治疗DHL和DEL治疗的治疗易受脆弱性。最近，我们使用A建模了DHL 包括骨髓基质和模仿DHL肿瘤微环境的平台。使用此平台 我们实施了基于非偏见的基于活动的蛋白质组学分析，药物筛选，RNA-seq和ChIP-Seq研究 确定在DHL中表现出的基本途径和目标。这些分析非常引人注目，表明 DHL具有独特的超级增强剂（SE）景观，其中SE在DHL中的表现与基因相关 控制淋巴瘤细胞命运或致癌信号传导。此外，这些屏幕显示DHL和DEL Cell 线条和原发性患者标本对一般转录设备的抑制剂高度敏感。在 特别是，所有DHL和DEL细胞都对THZ1非常敏感，THZ1是一种新近鉴定的细胞周期蛋白的共价抑制剂 依赖性激酶7（CDK7）作为转录共同因素，并磷酸化C末端 RNA聚合酶-II的结构域。此外，我们对CDK9产生的NVP2选择性抑制剂的研究表明 DHL和DEL细胞的存活也需要该激酶的活性，该激酶调节转录 伸长。值得注意的是，我们的新发现已经确定CDK7和CDK90功能对于 在DHL和DEL模型中保持MYC的表达。我们假设Myc-，cdk7-和cdk9-- 依赖转录和BCL-2过表达合作驱动了侵略性表型 DHL和DEL以及相应地，将CDK7或CDK9和BCL-2触发的抑制作用合成合成 这些侵略性淋巴瘤中的致死性。使用我们的基于单元的平台DHL和DEL Cell Line模型DHL 我们的实验室中可用的患者衍生异种移植物（PDX）和合成小鼠DHL模型 各自的专业知识，以及我们独特地访问大量主要DHL患者标本，我们将解决 CDK7和CDK9在维持DHL中的作用，我们将定义CDK7/CDK9的机制 在这种致命的恶性肿瘤中维持致癌驱动因素的表达。最后，我们将战略性地针对 转录机械和前链链接验证一种结合禁用药物的治疗策略 CDK7，CDK9和BCL2是治疗DHL和DEL的合成治疗方法。呢

项目成果

MCL-1 dependency as a novel vulnerability for aggressive B cell lymphomas.

• DOI: 10.1038/s41408-020-00402-2
• 发表时间: 2021-01-14
• 期刊: Blood cancer journal
• 影响因子: 12.8
• 作者: Wang MY;Li T;Ren Y;Shah BD;Lwin T;Gao J;Shain KH;Zhang W;Zhao X;Tao J
• 通讯作者: Tao J