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

Author:

Plotnik Joshua P.1ORCID,Richardson Adam E.1ORCID,Yang Haopeng2ORCID,Rojas Estela2ORCID,Bontcheva Velitchka1ORCID,Dowell Colleen1ORCID,Parsons Sydney2ORCID,Wilson Ashley2ORCID,Ravanmehr Vida2ORCID,Will Christine1ORCID,Jung Paul1ORCID,Zhu Haizhong1ORCID,Partha Sarathy Karunan1ORCID,Panchal Sanjay C.1ORCID,Mali Raghuveer Singh3ORCID,Kohlhapp Frederick J.1ORCID,McClure Ryan A.1ORCID,Ramathal Cyril Y.1ORCID,George Mariam D.1ORCID,Jhala Manisha1ORCID,Elsen Nathaniel L.1ORCID,Qiu Wei1ORCID,Judge Russell A.1ORCID,Pan Chin3ORCID,Mastracchio Anthony1ORCID,Henderson Jared2ORCID,Meulbroek Jonathan A.1ORCID,Green Michael R.2ORCID,Pappano William N.1ORCID

Affiliation:

1. AbbVie Inc., North Chicago, Illinois. 1

2. Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas. 2

3. AbbVie Bay Area, South San Francisco, California. 3

Abstract

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.

Funder

AbbVie

Publisher

American Association for Cancer Research (AACR)

Reference43 articles.

1. Epidemiology of non-Hodgkin’s lymphoma;Thandra;Medical Sci,2021

2. Non-Hodgkin’s lymphoma: a review;Singh;J Fam Medicine Prim Care,2020

3. Genetics and pathogenesis of diffuse large B-cell lymphoma;Schmitz;New Engl J Medicine,2018

4. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes;Chapuy;Nat Med,2018

5. Genetic landscapes of relapsed and refractory diffuse large B-cell lymphomas;Morin;Clin Cancer Res,2016

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3