A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy

Year: 2024

Type: article

Abstract: Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs — an effective treatment for lymphomas — has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 ( 3 ) showed a favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53 showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8 + to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Transcriptomic analysis revealed that STR-V-53 primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy. Graphical Abstract

Source: ACS Pharmacology & Translational Science

DOI: 10.1021/acsptsci.4c00358

Authors: Bocheng Wu, Subhasish Tapadar, Zhiping Ruan, Carrie Q. Sun, Rebecca S. Arnold, Alexis Johnston, Jeremiah O. Olugbami, Uche Arunsi, David A. Gaul, John A. Petros, Tatsuya Kobayashi, Dan G. Duda, Adegboyega K. Oyelere

Institutions: Georgia Institute of Technology, Harvard University, Massachusetts General Hospital, First Affiliated Hospital of Xi'an Jiaotong University, Emory University

Language: English

Topic: Histone Deacetylase Inhibitors Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: U.S. Department of Defense, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Georgia Institute of Technology, Exelixis, National Institutes of Health, National Cancer Institute, DOD Peer Reviewed Cancer Research Program

OpenAlex ID: W4402269159