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.

获得性耐药性（DR）在很大程度上限制了靶向癌症治疗的有效性，特别是对于侵袭性疾病，例如套细胞淋巴瘤 (MCL)，这是一种预后不良的 B 细胞淋巴瘤。最近， FDA 批准的药物 Venetoclax (ABT-199) 是一种新型、有效的、选择性的小分子 BCL-2 抑制剂经临床检验，可作为造血系统肿瘤（包括 MCL）的有效治疗方法。 ABT-199的用途产生了戏剧性的反响；然而，对这种药物的耐药性的出现导致了致命的后果。 MCL 的进展。一旦 MCL 患者在 ABT-199 治疗期间或之后复发，就会出现疾病进展迅速，死亡率加速。因此，迫切需要明确机制 ABT-199 耐药性 (AR) 并确定目标，提出具有切实疗效的新治疗方案潜在的。我们通过从 MCL 生成 AR 细胞系来模拟 ABT-199 的耐药性，并表征这些细胞中针对 ABT-199 治疗的适应性分子重编程。淋巴瘤的小亚群一致检测到细胞通过输入可逆药物来逃避强选择性 ABT-199 压力容忍“持久”状态（DTP），从而导致 DTP 扩展种群（DTEP）并最终获得真正的耐药性。鉴于 MCL 涉及多种机制的前提 AR，我们应用全网络、稳健且公正的方法来确定主要改变的 MCL 信号传导 AR进化过程中的路径。我们观察到，比我们预期的更复杂、更动态这些 DTEP 细胞具有与 BH3 家族蛋白相关的活力和克隆生长能力增强重新编程。有趣的是，DTEP细胞在长期传代后可以恢复到药物敏感状态没有药物，支持这些细胞通过表观遗传重新编程而产生耐药性的观点州。与这些结果一致，我们的初步药物筛选揭示了对表观遗传的精致敏感性与亲代细胞相比，ABT-199 DTEP 细胞中的机械抑制剂（例如 BRD4、CDK7）。排队由此，我们的免疫沉淀测序 (ChIP-Seq) 和 RNA-Seq 检测揭示了动态超级 DTEP MCL 细胞中的增强子 (SE) 重塑，这种染色质改变与 CDK7 介导的相关 ABT-199 耐药 MCL 细胞中的转录。我们提出转录和表观遗传适应性细胞在 ABT-199 治疗下持续存活需要反应。目标该提案的目的是战略性地瞄准转录机制并通过以下方式提供临床前验证靶向 CDK7/BRD4 与 BCL-2 联合作为 MCL 的有效且持久的治疗方法。随着 Qi 和中提供用于表观遗传靶标和患者来源的异种移植 (PDX) 模型的小分子工具 Tai 实验室、各自的专业知识以及对大量初级 MCL 样本资源的独特获取方式，研究使我们能够获得对 MCL 耐药生物学的宝贵见解并揭示一种新的机制 - MCL 患者的驱动疗法。