Therapeutic targeting of SIRT3 for aggressive and refractory lymphomas

摘要 在侵袭性淋巴瘤中，弥漫性大B细胞淋巴瘤（DLBCL）是其中之一。 增殖性最高，并且对代谢前体的产生具有大量需求。 沿着这些路线，我们最近确定了NAD+依赖性赖氨酸脱乙酰酶SIRT 3，作为一个主酶， 线粒体应激代谢的调节剂，作为DLBCL生长的关键驱动因素， 生存我们发现DLBCL细胞中SIRT3功能的丧失通过破坏淋巴瘤细胞的增殖而杀死淋巴瘤。 它们在TCA循环中使用谷氨酰胺和其他氨基酸的能力， 自噬-在体外和体内。重要的是，我们创造了线粒体靶向SIRT3 选择性小分子YC 8 - 02，精确模拟SIRT3耗竭的作用， 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作用 与靶向治疗如维奈托克以及化疗药物联合 通常用于治疗DLBCL。最后，我们的机制数据指出， 最终可能导致对SIRT3靶向治疗的耐药性，以及预防这种耐药性的方法。 以产生最大的治疗效果。一个首要的挑战， 为DLBCL患者提供精准药物是他们显著的遗传异质性， 大量的体细胞突变目前没有有活动的目标代理 和与一小部分患者相关的靶点。然而，我们发现SIRT3 作为DLBCL所需的广泛相关和关键的非癌基因成瘾 独立于他们的基因背景。通过这一建议，我们为i） 将SIRT3抑制剂转化为临床，ii）了解和减轻潜在的耐药性 iii）将SIRT3抑制剂掺入合理设计的抗淋巴瘤药物中， 对于迫切需要改善的患者亚群具有广泛相关性的方案 治疗我们的建议使用与这些生理学相关的最先进的模型系统 复杂的肿瘤，并准备提供高度影响力的结果，从科学和临床 perspective.

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.