Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.

IF 5.3 2区医学 Q1 ONCOLOGY

Molecular Cancer Therapeutics Pub Date : 2024-07-02 DOI:10.1158/1535-7163.MCT-23-0518

Joshua P Plotnik, Adam E Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan Partha, Sanjay C Panchal, Raghuveer Singh Mali, Frederick J Kohlhapp, Ryan A McClure, Cyril Y Ramathal, Mariam D George, Manisha Jhala, Nathaniel L Elsen, Wei Qiu, Russell A Judge, Chin Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano

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引用次数: 0

Abstract

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

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在 B 细胞淋巴瘤模型中抑制 MALT1 和 BCL2 可诱导协同抗肿瘤活性。

弥漫大B细胞淋巴瘤（DLBCL）的活化B细胞（ABC）亚群以慢性B细胞受体信号传导为特征，接受标准疗法治疗后疗效不佳。在ABC-DLBCL中，MALT1是一种核心酶，会因B细胞受体的刺激或信号通路上游成分的功能增益突变而被持续激活，使其成为一个有吸引力的治疗靶点。我们发现了一种新型小分子抑制剂 ABBV-MALT1，它能在 ABC-DLBCL 临床前模型中选择性地有效关闭 B 细胞信号传导，从而有效抑制细胞生长和异种移植。我们还发现了ABBV-MALT1与BCL2抑制剂venetoclax的合理联用伙伴，两者联用可显著增效，在临床前模型中激发深入持久的反应。这项工作凸显了ABBV-MALT1单药治疗和与venetoclax联用作为ABC-DLBCL患者有效治疗方案的潜力。

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

Molecular Cancer Therapeutics 医学-肿瘤学

CiteScore

11.20

自引率

1.80%

发文量

331

审稿时长

3 months

期刊介绍： Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.