Targeting SIRT1 in Mantle Cell Lymphoma

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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.