Chromatin remodeling and FOXO in targeting CDK4 in mantle cell lymphoma

染色质重塑和 FOXO 在套细胞淋巴瘤中靶向 CDK4

基本信息

批准号：
9524114
负责人：
SELINA Y CHEN-KIANG
金额：
$ 38.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-02 至 2018-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9524114
关键词：
Address Agammaglobulinaemia tyrosine kinase Attenuated B-Cell NonHodgkins Lymphoma B-Lymphocytes Biological Assay Bortezomib CDK4 gene Cause of Death Cell Cycle Cell Cycle Regulation Cell Death Cell Line Cell Nucleus Cells Chromatin Chromosomal translocation Clinical Clinical Trials Combined Modality Therapy Complex Cyclin D1 Cyclin-Dependent Kinase Inhibitor 2A Development Disease Disease Progression Drug resistance EZH2 gene Enhancers Epigenetic Process Event FOXO1A gene G1 Arrest Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Homeostasis Human In Vitro Light Lymphoma Malignant Neoplasms Mantle Cell Lymphoma Mediating Metabolism Modeling Mutation Oxidation-Reduction Patients Phase Phase I Clinical Trials Phase II Clinical Trials Polycomb Receptors, Antigen, B-Cell Recurrence Regulation Resistance Role Signal Transduction Stress Testing Time Transposase Tumor Suppressor Proteins base cancer cell cancer therapy chromatin remodeling clinical efficacy cytotoxic drug development exome sequencing gain of function histone methyltransferase improved in vivo inhibitor/antagonist loss of function neoplastic cell novel prevent promoter response targeted agent transcription factor transcriptome transcriptome sequencing tumor

项目摘要

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin lymphoma (NHL) that remains largely incurable due to development of drug resistance. Disease progression in MCL is invariably associated with unrestrained proliferation of tumor cells caused by dysregulated CDK4 activity and aberrant cyclin D1 expression. Targeting CDK4, therefore, is a rational approach to MCL therapy. The first phase I clinical trial targeting CDK4 with PD 0332991 (palbociclib, the first selective CDK4/6 inhibitor) in recurrent MCL resulted in durable clinical responses with tumor regression in some MCL patients. Inhibition of CDK4, therefore, not only prevents proliferation of cancer cells but also enhances their vulnerability. Ongoing clinical trials combining palbociclib with bortezomib or with ibrutinib, which inhibits BTK required for MCL survival, support the clinical efficacy of targeting CDK4. Longitudinal integrative analysis of whole transcriptome–sequencing and whole exom- sequencing further reveals that inhibition of CDK4 leads to prolonged early G1 arrest (pG1) in all patients but clinical response is associated with differential regulation of genes that are involved in PI3K inactivation, metabolism and redox stress. To address the underlying mechanism, we discovered that pG1 induced repressive chromatin remodeling by differential regulation of EZH1 and EZH2, histone methyltransferases for H3K27me2/3, in responding patients, and timely inhibition of EZH1/EZH2 led to synergistic killing of MCL cells in pG1. These results suggest that chromatin remodeling is a critical proximal event in pG1 reprogramming. Moreover, pG1 sensitizes MCL cells to killing by ibrutinib and by inhibition of PI3K, and this requires the action of the FOXO1 transcription factor, which is activated and localized to the nucleus in pG1. FOXO1 is a central component of the PI3K signaling and also acts as a tumor suppressor in a context-dependent manner. Based on our novel preliminary findings, we hypothesize that induction of pG1 by CDK4 inhibition causes specific epigenetic alterations that modify FOXO1's access to its target genes, which in turn alters the expression of FOXO1-dependent cytotoxic genes for clinical response to targeting CDK4 in MCL. Our goal is to advance hypothesis-driven, effective and durable cell cycle therapy in cancer by defining the mechanisms of cell cycle reprogramming. To achieve this goal, we will test our hypothesis in two Specific Aims: 1) To elucidate the role of EZH1 and EZH2 in chromatin remodeling in pG1 reprogramming by elucidate chromatin remodeling in pG1 transcriptional reprogramming and determining the functional consequence of cell cycle regulation of EZH1/EZH2; and 2) To define the role of FOXO1 in CDK4 inhibitor sensitization to BTK or PI3K inhibition by determine the significance of cell cycle regulation of FOXO1 and identifying the transcriptional targets of FOXO1 that mediates pG1 sensitization to clinical response. Successful completion of the proposed studies should shed light on the mechanism of cell cycle control of chromatin remodeling and FOXO activation, which has important and broad clinical implications.

套细胞淋巴瘤 (MCL) 是一种 B 细胞非霍奇金淋巴瘤 (NHL)，由于以下原因在很大程度上仍无法治愈： MCL 的疾病进展总是与不受限制有关。 CDK4 活性失调和细胞周期蛋白 D1 靶向表达异常引起的肿瘤细胞增殖。因此，CDK4 是 MCL 治疗的合理方法第一个针对 CDK4 治疗 PD 的 I 期临床试验。 0332991（palbociclib，第一个选择性 CDK4/6 抑制剂）在复发性 MCL 中产生了持久的临床效果因此，抑制 CDK4 不仅可以预防某些 MCL 患者的肿瘤消退。正在进行的联合 palbociclib 的临床试验会增加癌细胞的增殖，但也会增加其脆弱性。与硼替佐米或依鲁替尼一起使用，可抑制 MCL 存活所需的 BTK，支持以下临床疗效靶向 CDK4 的全转录组测序和全外显子组的纵向整合分析。测序进一步表明，CDK4 的抑制会导致所有患者的早期 G1 停滞 (pG1) 延长，但临床反应与参与 PI3K 失活的基因的差异调节有关，为了解决潜在的机制，我们发现 pG1 诱导。通过 EZH1 和 EZH2、组蛋白甲基转移酶的差异调节抑制染色质重塑 H3K27me2/3，在有反应的患者中，及时抑制 EZH1/EZH2 导致对 MCL 细胞的协同杀伤这些结果表明染色质重塑是 pG1 重编程中的关键近端事件。此外，pG1 使 MCL 细胞对 ibrutinib 和 PI3K 抑制的杀伤敏感，这需要采取行动 FOXO1 转录因子在 pG1 中被激活并定位于细胞核，是一个核心。 PI3K 信号传导的组成部分，并且还以基于上下文的方式充当肿瘤抑制因子。根据我们新的初步发现，我们发现通过 CDK4 抑制诱导 pG1 会导致特定的表观遗传改变改变了 FOXO1 对其靶基因的访问，进而改变了 FOXO1 依赖性细胞毒性基因对 MCL 中靶向 CDK4 的临床反应我们的目标是推进。通过定义细胞周期机制，以假设为驱动的、有效且持久的癌症细胞周期疗法为了实现这一目标，我们将在两个具体目标中检验我们的假设：1）阐明通过阐明染色质，EZH1 和 EZH2 在 pG1 重编程染色质重塑中的作用 pG1 转录重编程的重塑并确定细胞周期的功能后果 EZH1/EZH2 的调节；以及 2) 确定 FOXO1 在 CDK4 抑制剂对 BTK 或通过确定 FOXO1 细胞周期调节的重要性并鉴定 PI3K 抑制 FOXO1 介导 pG1 对临床反应敏感的转录靶点成功完成。拟议的研究应阐明染色质重塑和细胞周期控制的机制 FOXO 激活，具有重要而广泛的临床意义。