Faculty, Staff and Student Publications

Publication Date

7-2-2024

Journal

Molecular Cancer Therapeutics

DOI

10.1158/1535-7163.MCT-23-0518

PMID

38507740

PMCID

PMC11217731

PubMedCentral® Posted Date

3-20-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Humans, Animals, Mice, Proto-Oncogene Proteins c-bcl-2, Drug Synergism, Xenograft Model Antitumor Assays, Cell Line, Tumor, Sulfonamides, Cell Proliferation, Lymphoma, Large B-Cell, Diffuse, Bridged Bicyclo Compounds, Heterocyclic, Antineoplastic Agents, Disease Models, Animal

Published Open-Access

yes

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