Targeting SIRT1 in Mantle Cell Lymphoma

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，非常难以治疗，患者的中位生存期约为5年。 虽然治疗方案是可用的，但患者经常复发，每次复发更难以治疗。目前，许多MCL的靶向治疗在诱导MCL细胞凋亡方面效率低下。因此，迫切需要新的治疗方法。 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类和II类HDAC的辛二酰苯胺异羟肟酸（SAHA）在临床前研究中显示出一些前景。然而，到目前为止，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SIRT 1（NAD+依赖性HDAC），调节代谢、生理稳态和应激反应，并且与年龄相关疾病（包括癌症）相关。尽管SIRT 1作为癌症治疗的药物靶标具有潜在的重要性，但关于SIRT 1的活性和功能的问题仍然没有答案。 在本申请中，我们的目标是推进SIRT 1的生物学功能的基本理解，并澄清SIRT 1是否可以作为MCL治疗的靶点。长期目标是将SIRT 1和Sirtuin抑制剂的基础研究成果转化为临床和以患者为导向的研究。我们的项目包括三个高度互动和相互依存的目标。目的1检测SIRT 1对MCL细胞DNA损伤修复途径中MRE 11-RAD 50-NBS 1（MRN）复合物的影响。这项工作可能揭示了SIRT 1调节组蛋白脱乙酰化以外的表观遗传变化的另一种新机制。更重要的是，这些研究可能有助于阐明靶向SIRT 1在MCL DNA损伤修复途径中的重要性。目的2将研究SIRT 1修饰两种乙酰转移酶hMOF和TIP 60的活性和功能的可能性。这项工作可以揭示SIRT 1直接参与DNA损伤修复的新概念，并在调节细胞凋亡中发挥作用，还通过调节DNA损伤期间hMOF和TIP 60的临界水平间接发挥作用，进一步验证Sirtuin抑制剂用于MCL治疗的潜在用途。目的3将验证Sirtuin抑制剂可以增强其他化疗药物（包括DNA损伤剂）对MCL的影响的假设。这项转化工作可能会提出新的治疗策略，可以在未来的临床试验中提出。 虽然理解和严格分析SIRT 1和Sirtuin抑制剂的共同主题在所有目标中产生共鸣，但提出了不同但互补的问题，最终目标是彻底理解SIRT 1的临床相关性，并最终将这些知识应用于诊断和治疗MCL治疗方法，以帮助推进MCL的治愈。

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.