Repurposing NAMPT inhibitors for germinal center B-cell-like diffuse large B-cell lymphoma.

IF 11.5 Q1 HEMATOLOGY Blood Cancer Discovery Pub Date : 2024-08-05 DOI:10.1158/2643-3230.BCD-24-0020

Claudio Scuoppo, Bowen Cai, Kenneth Ofori, Hanna Scholze, Rahul Kumar, Angelo D'Alessandro, Katia Basso, Laura Pasqualucci, Riccardo Dalla-Favera

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Abstract

Diffuse Large B-cell lymphoma (DLBCL) includes the Activated B-cell-like (ABC) and Germinal Center B-cell-like (GCB) subtypes, which differ in cell-of-origin, genetics and clinical response. By screening the subtype-specific activity of 211 drugs approved or in active clinical development for other diseases, we identified inhibitors of nicotinamide phosphoribosyl transferase (NAMPTi) as active in a subset of GCB-DLBCLs in vitro and in vivo. We validated three chemically distinct NAMPTi for their on-target activity based on biochemical and genetic rescue approaches, and found the ratio between NAMPT:PARP1 RNA levels was predictive of NAMPTi sensitivity across DLBCL subtypes. Notably, the NAMPT:PARP1 transcript ratio predicts higher anti-tumor activity in BCL2-translocated GCB-DLBCL. Accordingly, pharmacological and genetic inhibition of BCL2 was potently synergistic with NAMPT blockade. These data support the inhibition of NAMPT as a therapeutically relevant strategy for BCL2-translocated DLBCLs.

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将 NAMPT 抑制剂重新用于治疗生殖中心 B 细胞样弥漫大 B 细胞淋巴瘤。

弥漫大B细胞淋巴瘤（DLBCL）包括活化B细胞样（ABC）亚型和生殖中心B细胞样（GCB）亚型，它们在起源细胞、遗传学和临床反应方面各不相同。通过筛选 211 种已获批准或正在临床开发中的治疗其他疾病的药物的亚型特异性活性，我们发现烟酰胺磷酸核糖转移酶（NAMPTi）抑制剂在体外和体内对 GCB-DLBCLs 亚型具有活性。我们根据生化和基因挽救方法验证了三种化学性质不同的 NAMPTi 的靶向活性，并发现 NAMPT:PARP1 RNA 水平之间的比率可预测 DLBCL 亚型对 NAMPTi 的敏感性。值得注意的是，NAMPT:PARP1转录本比率预示着BCL2转座的GCB-DLBCL具有更高的抗肿瘤活性。因此，BCL2的药理和基因抑制与NAMPT阻断具有强大的协同作用。这些数据支持将抑制NAMPT作为一种治疗BCL2转移的DLBCL的相关策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Blood Cancer Discovery Multiple-

CiteScore

12.70

自引率

1.80%

发文量

139

期刊介绍： The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.