Therapeutic targeting of SIRT3 for aggressive and refractory lymphomas

SIRT3 治疗侵袭性和难治性淋巴瘤的靶向治疗

基本信息

批准号：
10587454
负责人：
ARI M. MELNICK
金额：
$ 67.99万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-02 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587454
关键词：
Acetyl Coenzyme A Amino Acids Apoptosis Autophagocytosis B-Lymphocytes Basic Science Biochemical Biochemical Pathway Biological Biological Assay Biological Models Biology Bypass Cells Chemoresistance Citric Acid Cycle Clinic Clinical Complex Data Deacetylase Deacetylation Enzymes Generations Genetic Genetic Heterogeneity Glutamine Growth Impairment In Vitro Inferior Intervention Knockout Mice Lead Link Lymphoma Lymphoma cell Lymphomagenesis Lysine Mediator Metabolic Metabolic Pathway Metabolism Mitochondria Mus Mutation Nutrient Outcome Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Physiological Precision therapeutics Production Proliferating Recurrence Refractory Regimen Reporting Research Resistance Role Sirtuins Somatic Mutation Stress Structure of germinal center of lymph node Text Therapeutic Translating Treatment Efficacy Tumor Suppressor Proteins Work cell killing chemotherapy clinical translation combinatorial effective therapy improved in vivo inhibitor knock-down large cell Diffuse non-Hodgkin&apos s lymphoma loss of function molecular targeted therapies novel overexpression patient subsets pharmacologic precision medicine prevent programs rational design resistance mechanism small molecule small molecule inhibitor targeted agent targeted treatment therapeutic target tumor

项目摘要

ABSTRACT Among aggressive lymphomas, the Diffuse large B-cell lymphomas (DLBCLs) are among the most highly proliferative, and have massive requirements for production of metabolic precursors. Along these lines we recently identified NAD+ dependent lysine deacetylase SIRT3, as a master regulator of mitochondrial stress metabolism, as a critical driver of DLBCL growth and survival. We showed that SIRT3 loss of function in DLBCL cells kills lymphomas by disrupting their ability to use glutamine and other amino acids in the TCA cycle, which triggers destructive autophagy – both in vitro and in vivo. Importantly, we created the mitochondrial targeted SIRT3 selective small molecule YC8-02 that precisely mimics the effect of SIRT3 depletion and potently killed DLBCL cells in vitro and in vivo. These compounds yielded further enhanced killing effects in combination with targeted therapies such as venetoclax as well with chemotherapy drugs commonly used to treat DLBCLs. Finally, our mechanistic data point to pathways in cells that could eventually lead to resistance to SIRT3 targeted therapy, as well as ways to prevent this from happening so as to yield maximal therapeutic efficacy. An overarching challenge in delivering precision medicine for DLBCL patients is their marked genetic heterogeneity and extreme abundance of somatic mutations. There are currently no targeted agents with activity and targets relevant to more than a small fraction of patients. However, we identified SIRT3 as a broadly relevant and critical non-oncogene addiction that is required by DLBCLs independent of their genetic background. Through this proposal we provide the basis for i) translating SIRT3 inhibitors to the clinic, ii) understanding and mitigating potential resistance mechanisms, and iii) incorporating SIRT3 inhibitors into rationally designed anti-lymphoma regimens with broad relevance for the subsets of patients who desperately need improved therapies. Our proposal uses state of the art model systems physiologically relevant to these complex tumors, and is poised to deliver highly impactful outcomes from the scientific and clinical perspective.

抽象的在侵袭性淋巴瘤中，弥漫性大B细胞淋巴瘤（DLBCL）是最高度增殖，并且对代谢前体的生产有巨大的要求。沿着这些线条，我们最近将NAD+依赖性赖氨酸脱乙酰基酶SIRT3确定为主人线粒体应力代谢的调节剂，是DLBCL增长和生存。我们表明，DLBCL细胞中SIRT3功能丧失通过破坏杀死淋巴瘤他们在TCA周期中使用谷氨酰胺和其他氨基酸的能力，这会触发破坏性自噬 - 体外和体内。重要的是，我们创建了线粒体靶向SIRT3 精确模拟SIRT3部署效果的选择性小分子YC8-02 在体外和体内杀死了DLBCL细胞。这些化合物产生了进一步增强的杀戮效果结合有针对性疗法（例如Venetoclax）以及化学疗法药物通常用于治疗DLBCL。最后，我们的机械数据指向细胞中的途径最终可能导致对SIRT3靶向疗法的抵抗，以及防止这种疗法的方法从发生以获得最大的治疗效率。在为DLBCL患者提供精确药物是其明显的遗传异质性和体细胞突变的极端抽象。当前没有活动的目标代理并与一小部分患者相关的目标。但是，我们确定了SIRT3 作为DLBCLS要求的广泛相关和关键的非癌基因成瘾独立于其遗传背景。通过此建议，我们为i提供了基础将SIRT3抑制剂转换为诊所，ii）理解和减轻潜在电阻机理，iii）将SIRT3抑制剂编码为合理设计的抗淋巴瘤对于迫切需要改进的患者的子集，具有广泛相关性的方案疗法。我们的建议使用与这些模型的最新模型系统的状态复杂的肿瘤，并被毒性从科学和临床中带来高度影响的结果看法。