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

• 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
• 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' 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

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) 属于 增殖能力最强，并且对代谢前体的产生有大量需求。 沿着这些思路，我们最近发现了 NAD+ 依赖的赖氨酸脱乙酰酶 SIRT3，作为主控 线粒体应激代谢的调节因子，是 DLBCL 生长的关键驱动因素 生存。我们发现，DLBCL 细胞中 SIRT3 功能丧失可通过破坏 他们在 TCA 循环中使用谷氨酰胺和其他氨基酸的能力，这会引发破坏性的 自噬——体外和体内。重要的是，我们创建了线粒体靶向 SIRT3 选择性小分子 YC8-02 精确模拟 SIRT3 耗竭的效果并有效 在体外和体内杀死DLBCL细胞。这些化合物产生了进一步增强的杀伤效果 与靶向治疗（如维奈托克）以及化疗药物联合使用 常用于治疗 DLBCL。最后，我们的机制数据指出了细胞中的途径 最终可能导致对 SIRT3 靶向治疗的耐药性，以及预防这种情况的方法 以免发生，从而产生最大的治疗效果。一项重大挑战 为 DLBCL 患者提供精准医疗的关键在于他们显着的遗传异质性和 体细胞突变极其丰富。目前没有具有活性的靶向药物 以及与一小部分患者相关的目标。然而，我们发现 SIRT3 作为 DLBCL 所需的广泛相关且关键的非癌基因成瘾 独立于他们的遗传背景。通过这个提案，我们为 i) 提供了基础 将 SIRT3 抑制剂转化为临床，ii) 了解并减轻潜在耐药性 机制，以及 iii) 将 SIRT3 抑制剂纳入合理设计的抗淋巴瘤药物中 与迫切需要改善的患者亚群具有广泛相关性的治疗方案 疗法。我们的建议使用与这些生理相关的最先进的模型系统 复杂的肿瘤，并准备提供具有高度影响力的科学和临床结果 看法。