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bioRxiv · 10.1101/2024.03.27.587062

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

Wu, B.·Tapadar, S.·Ruan, Z.·Sun, C.·Arnold, R.·Olugbami, J.·Johnston, A.·Arunsi, U.·Gaul, D.·Petros, J.·Kobayashi, T.·Duda, D. G.·Oyelere, A. K.
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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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/587062v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@28281corg.highwire.dtl.DTLVardef@617aa9org.highwire.dtl.DTLVardef@1bc198dorg.highwire.dtl.DTLVardef@31852e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wu, B., Tapadar, S., Ruan, Z., Sun, C., Arnold, R., Olugbami, J., Johnston, A., Arunsi, U., Gaul, D., Petros, J., Kobayashi, T., Duda, D. G., Oyelere, A. K.. 2024-03-28. A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy. https://doi.org/10.1101/2024.03.27.587062

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