Targeting SIRT1 in Mantle Cell Lymphoma

套细胞淋巴瘤中的 SIRT1 靶向治疗

基本信息

批准号：
9068864
负责人：
EDWARD SETO
金额：
$ 21.31万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-03 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9068864
关键词：
Accounting Acetylation Acetyltransferase Address Affect Age Apoptosis Apoptotic B-Cell NonHodgkins Lymphoma B-Lymphocytes BCL6 gene Basic Science Biological Biological Process Burkitt Lymphoma Cell Line Cells Clinic Clinical Clinical Trials Complex DNA Damage DNA Double Strand Break DNA Repair Deacetylation Diagnostic Diffuse Disease Doxorubicin Drug Targeting Enzymes Epigenetic Process Excision Exhibits Future Goals HTATIP gene Health Histone Deacetylase Inhibitor Histone Deacetylation Histones Homeostasis Human Individual Knowledge Laboratories Link Lysine MCL1 gene Malignant Neoplasms Mantle Cell Lymphoma Mediating Metabolism Modeling Molecular NBS1 gene Non-Hodgkin&apos s Lymphoma Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Physiological Play Prognostic Marker Property Protein Kinase Proteins Receptor Signaling Receptors, Antigen, B-Cell Refractory Regimen Relapse Reporting Research Research Personnel Role Science Signal Pathway Signal Transduction Sirtuins Specimen Survival Rate Testing Therapeutic Therapeutic Agents Treatment Protocols Ubiquitination United States Vorinostat Work alternative treatment base biological adaptation to stress clinically relevant conventional therapy epigenetic regulation falls functional group histone acetyltransferase improved outcome inhibitor/antagonist leukemia multicatalytic endopeptidase complex non-histone protein novel novel therapeutics nuclease outcome forecast patient oriented research preclinical study response sensor tandem mass spectrometry targeted agent targeted cancer therapy targeted treatment treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Mantle cell lymphoma (MCL), a subtype of non-Hodgkin's lymphoma, is extremely difficult to treat, with patient median survival of about 5 years. Although treatment regimens are available, patients often relapse, with each relapse more difficult to treat. Currently, many targeted therapies for MCL are inefficient on their own at inducing apoptosis in MCL cells. Thus, new treatment approaches are much needed. Investigators have recently explored HDAC inhibitors, agents that target epigenetic regulation, as new treatment. For example, suberoylanilide hydroxamic acid (SAHA), which inhibits Class I and II HDACs, has shown some promise in preclinical studies. So far, however, very little is known about the Class III HDACs (Sirtuins) and their potential as a target in MCL treatment. Sirtuins, particularly SIRT1 (a NAD+-dependent HDAC), regulate metabolism, physiological homeostasis, and stress responses and are linked to age- associated diseases, including cancer. Despite its potential importance as a drug target for cancer therapy, questions remain unanswered regarding the activities and functions of SIRT1. In this application, our objective is to advance the basic understanding of SIRT1's biological functions and to clarify whether SIRT1 can be targeted for MCL treatment. The long-term goal is to transfer the knowledge from basic research findings of SIRT1 and Sirtuin inhibitors to clinical and patient-oriented research. Our project consists of 3 highly interactive and interdependent aims. Aim 1 will test the effects of SIRT1 on the MRE11-RAD50-NBS1 (MRN) complex in DNA damage repair pathways in MCL cells. This work could potentially reveal an alternative, novel mechanism by which SIRT1 regulates epigenetic changes beyond the deacetylation of histones. More importantly, these studies may help elucidate the importance of targeting SIRT1 in DNA damage repair pathways in MCL. Aim 2 will examine the possibility that SIRT1 modifies the activities and functions of two acetyltransferases, hMOF and TIP60. This work could unveil the novel concept that SIRT1 is directly involved in DNA damage repair and has a role in regulating apoptosis and also functions indirectly by regulating a critical level of hMOF and TIP60 during DNA damage, further validating the potential use of Sirtuin inhibitors for MCL treatment. Aim 3 will test the hypothesi that Sirtuin inhibitors could enhance the impact of other chemotherapeutic drugs, including DNA-damaging agents, in MCL. This translational work may suggest novel treatment strategies that can be proposed in future clinical trials. Although the common theme of understanding and rigorously analyzing SIRT1 and Sirtuin inhibitors resonates in all aims, different yet complementary sets of questions are raised, with the ultimate goal of thoroughly understanding the clinical relevance of SIRT1 and eventually applying that knowledge into diagnostic and therapeutic MCL treatment approaches to help advance the cure of MCL.

描述（由申请人提供）：套细胞淋巴瘤（MCL）是非霍奇金淋巴瘤的一种亚型，治疗起来极其困难，患者的中位生存期约为 5 年。尽管有可用的治疗方案，但患者经常会复发，而且每次复发都更加难以治疗。目前，许多针对 MCL 的靶向疗法本身在诱导 MCL 细胞凋亡方面效率较低。因此，非常需要新的治疗方法。研究人员最近探索了 HDAC 抑制剂，即针对表观遗传调控的药物，作为新的治疗方法。例如，抑制 I 类和 II 类 HDAC 的辛二酰苯胺异羟肟酸 (SAHA) 在临床前研究中已显示出一些前景。然而，到目前为止，人们对 III 类 HDAC（Sirtuins）及其作为 MCL 治疗靶点的潜力知之甚少。 Sirtuins，特别是 SIRT1（一种 NAD+ 依赖性 HDAC），调节新陈代谢、生理稳态和应激反应，并与包括癌症在内的年龄相关疾病有关。尽管 SIRT1 作为癌症治疗的药物靶点具有潜在的重要性，但有关 SIRT1 的活性和功能的问题仍未得到解答。在本次应用中，我们的目标是增进对 SIRT1 生物学功能的基本了解，并阐明 SIRT1 是否可以靶向 MCL 治疗。长期目标是将 SIRT1 和 Sirtuin 抑制剂的基础研究成果的知识转移到临床和以患者为导向的研究中。我们的项目由 3 个高度互动且相互依赖的目标组成。目标 1 将测试 SIRT1 对 MCL 细胞 DNA 损伤修复途径中 MRE11-RAD50-NBS1 (MRN) 复合物的影响。这项工作可能揭示一种替代的新颖机制，SIRT1 通过该机制调节组蛋白脱乙酰化之外的表观遗传变化。更重要的是，这些研究可能有助于阐明靶向 SIRT1 在 MCL DNA 损伤修复途径中的重要性。目标 2 将检查 SIRT1 修饰两种乙酰转移酶 hMOF 和 TIP60 的活性和功能的可能性。这项工作揭示了SIRT1直接参与DNA损伤修复、调节细胞凋亡以及在DNA损伤过程中通过调节hMOF和TIP60的关键水平间接发挥作用的新概念，进一步验证了Sirtuin抑制剂治疗MCL的潜在用途治疗。目标 3 将检验这样的假设：Sirtuin 抑制剂可以增强其他化疗药物（包括 DNA 损伤剂）对 MCL 的影响。这项转化工作可能会提出可在未来临床试验中提出的新治疗策略。尽管理解和严格分析 SIRT1 和 Sirtuin 抑制剂的共同主题在所有目标中都引起共鸣，但提出了不同但互补的问题，最终目标是彻底了解 SIRT1 的临床相关性，并最终将这些知识应用于诊断和治疗性 MCL 治疗帮助推进 MCL 治愈的方法。