Transcriptional and Epigenetic Adaptation as Novel Therapeutic Vulnerabilities for Mantle Cell Lymphoma

转录和表观遗传适应作为套细胞淋巴瘤的新治疗漏洞

基本信息

批准号：
10579255
负责人：
Derek Ronald Duckett
金额：
$ 48.73万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579255
关键词：
Acceleration Atlases B lymphoid malignancy B-Cell Lymphomas BCL1 Oncogene BCL2L1 gene Back Biological Assay Biology Cell Line Cell Survival Cells Chemicals Chromatin Clinical Clinical Trials Collaborations Combined Modality Therapy Complex Development Disease Disease Progression Drug Modelings Drug Screening Drug Targeting Drug Tolerance Drug resistance Effectiveness Enhancers Epigenetic Process Evolution FDA approved Genetic Genetic Transcription Growth Hematopoietic Neoplasms Heterogeneity Human Immunoprecipitation Institution Joints Laboratories Lymphoma Lymphoma cell Malignant Neoplasms Mantle Cell Lymphoma Mediating Modeling Molecular Mus Nature Pathway interactions Patients Pharmaceutical Preparations Population Prognosis Protein Family Publishing Qi Relapse Resistance Resistance development Resources STAT3 gene Sampling Signal Pathway Technology Therapeutic Translations Up-Regulation Validation Work Xenograft procedure acquired drug resistance antagonist attenuation chromatin remodeling clinical remission clinical translation combat combinatorial drug resistance development drug-sensitive effective therapy experience improved improved outcome in vivo in vivo Model inhibitor insight lymphoid organ mortality novel novel therapeutics patient derived xenograft model pre-clinical preclinical study pressure prevent relapse patients resistance mechanism response small molecule standard care targeted cancer therapy therapeutically effective tool transcriptome transcriptome sequencing

项目摘要

Acquired drug resistance (DR) largely limits the effectiveness of targeted cancer therapies, especially for aggressive diseases, such as mantle cell lymphoma (MCL), a B-cell lymphoma with poor prognosis. Recently, FDA approved drug Venetoclax (ABT-199), a novel, potent and selective small-molecule BCL-2 inhibitor was clinically vetted as an effective therapy for hematopoietic tumors, including MCL. The use of ABT-199 produced a dramatic response; however, the emergence of resistance to this drug was ensued by fatal progression of the MCL. Once MCL patients relapse from ABT-199 treatment, either during or after, there is rapid disease progression and accelerated mortality. Thus, there is an urgent need to define mechanisms of ABT-199 resistance (AR) and identify targets to bring forward novel treatment options with tangible curative potential. We modeled drug resistance to ABT-199 by generating AR cell lines from MCL, and characterized the adaptive molecular reprogramming to ABT-199 treatment in these cells. Small subpopulations of lymphoma cells were consistently detected that evade strong selective ABT-199 pressure by entering a reversible drug tolerant 'persister' state (DTP), and consequently leading to a DTP expansion population (DTEP) and eventual acquisition of bona fide drug resistance. Given the premise that a myriad of mechanisms are involved in MCL AR, we applied network-wide, robust and unbiased approaches to determine the major altered MCL signaling pathways during AR evolution. More complex and more dynamic than we had anticipated, we observed that these DTEP cells conferred increased viability and clonogenic growth, associated with BH3 family protein reprogramming. Intriguingly, DTEP cells can revert back to drug sensitive states after long-term passaging without the drug, supporting the notion that these cells are epigenetically reprogrammed to drug resistant states. Consistent with these results, our initial drug screen revealed the exquisite sensitivity to epigenetic machinery inhibitors (e.g., BRD4, CDK7) in ABT-199 DTEP cells when compared with parental cells. In line with this, our immunoprecipitation-sequencing (ChIP-Seq) and RNA-Seq assays revealed dynamic super enhancer (SE) remodeling in DTEP MCL cells, and this chromatin alteration is associated with CDK7-mediated transcription in ABT-199 resistant MCL cells. We propose that transcriptional and epigenetic adaptive responses are required for the survival of cells that persist in the presence of ABT-199 therapy. The objective of this proposal is to strategically target transcriptional machinery and provide pre-clinical validation by targeting CDK7/BRD4, in combination with BCL-2 as an efficient and durable treatment for MCL. With the small molecule tools for epigenetic targets and patient-derived xenograft (PDX) model available in the Qi and Tao laboratories, respective expertise and the unique access to a large resource of primary MCL samples, the study allows us to gain valuable insights into MCL drug resistance biology and uncover a novel mechanism- driven therapy for MCL patients.

获得的耐药性（DR）在很大程度上限制了靶向癌症疗法的有效性，尤其是针对侵袭性疾病，例如斜膜细胞淋巴瘤（MCL），预后不良的B细胞淋巴瘤。最近， FDA批准的药物venetoclax（ABT-199），一种新颖，有效和选择性的小分子Bcl-2抑制剂是临床审查是包括MCL在内的造血肿瘤的有效疗法。使用ABT-199 产生了戏剧性的反应；但是，致命的出现对这种药物的抗性发生 MCL的进展。一旦MCL患者从ABT-199治疗中复发，无论是在快速疾病进展和加速死亡率。因此，迫切需要定义 ABT-199抗药性（AR）并确定具有切实治疗的新型治疗选择的靶标潜在的。我们通过从MCL产生AR细胞系对ABT-199的耐药性建模，并表征这些细胞中ABT-199处理的自适应分子重编程。淋巴瘤的小亚群始终检测到细胞通过进入可逆药物来逃避强烈的选择性ABT-199压力耐受性“持久”状态（DTP），因此导致DTP扩张人群（DTEP）和最终获取真正的耐药性。考虑到MCL涉及无数机制的前提 AR，我们应用网络范围内，鲁棒和公正的方法来确定主要改变的MCL信号传导 AR进化过程中的途径。比我们预期的更复杂，更动态，我们观察到这些DTEP细胞赋予了与BH3家族蛋白有关的生存力和克隆生长的增长重新编程。有趣的是，长期传播后，DTEP细胞可以恢复到药物敏感状态没有药物，支持这些细胞表观遗传重编程为抗药性的观念国家。与这些结果一致，我们的初始药物屏幕揭示了对表观遗传学的灵敏度与亲本细胞相比，ABT-199 DTEP细胞中的机械抑制剂（例如BRD4，CDK7）。排队这样，我们的免疫沉淀 - 测序（chip-seq）和RNA-seq分析显示了动态超级 DTEP MCL细胞中的增强剂（SE）重塑，并且该染色质的改变与CDK7介导在ABT-199抗性MCL细胞中的转录。我们提出了转录和表观遗传自适应在ABT-199治疗存在下持续存在的细胞存活需要反应。目标该建议的是战略性地针对转录机械，并通过靶向CDK7/BRD4，将BCL-2结合在一起，作为MCL的有效耐用处理。与 Qi和陶实验室，各自的专业知识以及对大量主要MCL样本资源的独特访问，研究使我们能够获得对MCL耐药性生物学的宝贵见解，并发现一种新型机制 - MCL患者的驱动疗法。