Project 2: Role of FOXO and Chromatin Remodeling in Cell Cycle Therapy for MCL

项目 2：FOXO 和染色质重塑在 MCL 细胞周期治疗中的作用

• 批准号: 10006523
• 负责人: Jihye Paik
• 金额: $ 29.91万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006523
• 关键词: 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; Cell physiology; Chromatin; Clinical; Clinical Trials; Collaborations; Complex; Cyclin D1; Cyclin-Dependent Kinase Inhibitor 2A; Cyclin-Dependent Kinases; Cytotoxic agent; Development; Disease Progression; Dose; Drug Targeting; Drug resistance; Enhancers; Epigenetic Process; Event; FOXO1A gene; G1 Arrest; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Homeostasis; Human; In Vitro; In complete remission; Light; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Modeling; Nuclear; Outcome; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphatidylinositols; Phosphotransferases; Polycomb; Promoter Regions; Receptors, Antigen, B-Cell; Recurrence; Resistance; Role; Sampling; Signal Transduction; Time; Transposase; Treatment Efficacy; Tumor Suppressor Proteins; base; cancer cell; cancer therapy; chromatin remodeling; cytotoxic; cytotoxicity; design; drug development; gain of function; improved; in vivo; kinase inhibitor; loss of function; mouse model; outcome forecast; overexpression; pre-clinical; programs; promoter; response; targeted agent; transcription factor; tumor

Project Summary Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma with an overall poor prognosis, and is currently incurable due to the eventual development of drug resistance. Unrestrained proliferation driven by cyclin D1 overexpression often underlies disease progression. The first phase I, single-agent clinical trial targeting the cyclin-dependent kinases CDK4/CDK6 with palbociclib treatment in recurrent MCL resulted in a durable clinical response, with tumor regression in some MCL patients. In ongoing clinical trials, palbociclib, in combination with other drugs targeting MCL survival is showing remarkable therapeutic efficacy, with many patients achieving a complete response at reduced doses. However, the mechanism by which CDK4/6 inhibition improves the efficacy of other targeted agents remains to be defined. Understanding this mechanism is critical to improving the response to these agents and overcoming resistance. In collaborative clinical and mechanistic studies with Project 1, we discovered that inhibition of CDK4/6 by palbociclib leads to prolonged early G1 arrest (pG1), which sensitizes cancer cells to cytotoxic killing by BTK or PI3K inhibition. This requires the action of FOXO1 transcription factor, which is activated and localized to the nucleus in pG1. Tumor suppressor FOXO1 is a central component of the PI3K signaling cascade engaged by the B cell receptor, and is essential for B cell homeostasis. We showed that FOXO1 expression and nuclear localization are necessary for cytotoxic killing by palbociclib in combination with a BTK or PI3K inhibitor. We found that pG1 induced repressive chromatin remodeling by the polycomb repressive complex 2 (PRC2), and that its perturbation induces synergistic killing of MCL cells in pG1. We hypothesize that pG1 induction by CDK4/6 inhibition in MCL cells causes specific epigenetic alterations that modify FOXO1 access to its target genes, altering FOXO1- mediated cytotoxic gene expression. We predict that timely perturbation of these epigenetic events should increase FOXO1 target gene expression, thus enhancing clinical outcomes of palbociclib and combined cytotoxic agent-induced killing. Hence our proposal will define the mechanisms underlying cytotoxic killing of MCL by targeting the cell cycle, and its coordinately regulated epigenetic and transcriptional machinery with specific aims (1) to elucidate the role of PRC2 in chromatin remodeling in pG1, and (2) to define the role of FOXO1 in CDK4 inhibitor sensitization to BTK or PI3K inhibition. Identification of downstream gene targets of FOXO1, and the cellular processes that they support, especially those that mediate cytotoxicity, will advance the rational design of mechanism-based, effective, and durable cancer therapies.

项目摘要 套细胞淋巴瘤（MCL）是一种总体预后不良的B细胞非霍奇金淋巴瘤， 由于最终产生耐药性，目前无法治愈。不受限制的扩散， 细胞周期蛋白D1的过度表达常常是疾病进展的基础。第一期单药临床试验 palbociclib治疗复发性MCL靶向细胞周期蛋白依赖性激酶CDK 4/CDK 6， 持久的临床反应，在一些MCL患者中肿瘤消退。在正在进行的临床试验中，palbociclib 与其他靶向MCL生存的药物联合使用显示出显著的治疗效果，许多 患者在降低剂量时达到完全缓解。然而，CDK 4/6 抑制提高其他靶向药物的功效仍有待确定。了解这种机制 对于改善对这些药剂的反应和克服耐药性至关重要。在协作临床和 在项目1的机制研究中，我们发现palbociclib对CDK 4/6的抑制作用导致 早期G1停滞（pG 1），其通过BTK或PI 3 K抑制使癌细胞对细胞毒性杀伤敏感。这需要 FOXO 1转录因子的作用，其在pG 1中被激活并定位于细胞核。肿瘤 抑制因子FOXO 1是由B细胞受体参与的PI 3 K信号级联的核心成分，并且 是B细胞稳态所必需的。我们发现FOXO 1的表达和核定位是必需的， palbociclib联合BTK或PI 3 K抑制剂的细胞毒性杀伤。我们发现pG 1诱导了 多梳抑制复合物2（PRC 2）抑制染色质重塑，其扰动 诱导协同杀伤pG 1中的MCL细胞。我们假设MCL中CDK 4/6抑制对pG 1的诱导作用 细胞引起特定的表观遗传改变，改变FOXO 1进入其靶基因，改变FOXO 1- 介导的细胞毒性基因表达。我们预测，这些表观遗传事件的及时扰动应该 增加FOXO 1靶基因表达，从而提高palbociclib和联合用药的临床结局 细胞毒性剂诱导的杀伤。因此，我们的建议将确定潜在的细胞毒性杀伤的机制， MCL通过靶向细胞周期，及其协同调节的表观遗传和转录机制， 具体目的是（1）阐明PRC 2在pG 1染色质重塑中的作用，以及（2）定义PRC 2在pG 1染色质重塑中的作用。 FOXO 1在CDK 4抑制剂对BTK或PI 3 K抑制的敏化中。下游基因靶标的鉴定 FOXO 1及其支持的细胞过程，特别是那些介导细胞毒性的过程， 合理设计基于机制的、有效的和持久的癌症疗法。