Targeting SIRT1 in Mantle Cell Lymphoma

套细胞淋巴瘤中的 SIRT1 靶向治疗

• 批准号: 8748681
• 负责人: EDWARD SETO
• 金额: $ 34.96万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 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/8748681
• 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; 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' s Lymphoma; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Physiological; Play; Prognostic Marker; Property; Protein Kinase; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Refractory; Regimen; Regulation; 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; cancer therapy; clinically relevant; conventional therapy; falls; functional group; histone acetyltransferase; improved; inhibitor/antagonist; leukemia; multicatalytic endopeptidase complex; novel; nuclease; outcome forecast; patient oriented research; preclinical study; public health relevance; response; sensor; tandem mass spectrometry; treatment strategy

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）：非霍奇金淋巴瘤的亚型地幔细胞淋巴瘤（MCL）非常困难，患者中位数的存活率约为5年。 尽管可以使用治疗方案，但患者通常会复发，每次复发更难以治疗。当前，许多针对MCL的靶向疗法本身在诱导MCL细胞凋亡时效率低下。因此，急需新的治疗方法。 研究人员最近探索了HDAC抑制剂，靶向表观遗传调节的药物，作为新的治疗方法。例如，抑制I和II级HDAC的Suberoylanilide羟氨基酸（SAHA）在临床前研究中表现出了一些希望。然而，到目前为止，对III级HDAC（SIRTUINS）及其作为MCL治疗目标的潜力知之甚少。 Sirtuins，特别是SIRT1（NAD+依赖性HDAC），调节代谢，生理稳态和压力反应，并与包括癌症在内的年龄相关疾病有关。尽管其作为癌症治疗的药物目标的重要性，但关于SIRT1的活动和功能的问题仍未得到解决。 在此应用中，我们的目标是提高对SIRT1生物学功能的基本了解，并阐明SIRT1是否可以针对MCL治疗。长期目标是将知识从SIRT1和SIRTUIN抑制剂的基础研究发现转移到临床和以患者为导向的研究。我们的项目由3个高度互动和相互依存的目标组成。 AIM 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。这项工作可能揭示出一种替代的新机制，通过该机制，SIRT1通过该机制调节超出组蛋白脱乙酰化的表观遗传变化。更重要的是，这些研究可能有助于阐明靶向SIRT1在MCL中DNA损伤修复途径中的重要性。 AIM 2将检查SIRT1修改两个乙酰转移酶HMOF和TIP60的活动和功能的可能性。这项工作可以公布新的概念，即SIRT1直接参与DNA损伤修复，并在调节凋亡中发挥作用，并通过调节DNA损伤期间的HMOF和TIP60的临界水平，从而进一步验证SIRTUIN抑制剂在MCL治疗中的潜在使用。 AIM 3将测试Sirtuin抑制剂可以增强MCL中其他化学治疗药物（包括DNA损害剂）的影响的假设。这项翻译工作可能表明可以在以后的临床试验中提出的新型治疗策略。 尽管理解和严格分析SIRT1和SIRTUIN抑制剂的共同主题在所有目的中都引起了共鸣，但提出了不同但互补的问题集，最终的目标是彻底了解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治疗方法中，以帮助推进MCL疗法。