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

Autor:	Wu B; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States., Tapadar S; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States.; Sophia Bioscience, Inc., 311 Ferst Drive NW, Ste. L1325A, Atlanta, Georgia 30332, United States., Ruan Z; Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School & Massachusetts General Hospital, Boston, Massachusetts 02114, United States.; Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Sun CQ; Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, United States., Arnold RS; Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, United States., Johnston A; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States., Olugbami JO; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States., Arunsi U; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States., Gaul DA; Sophia Bioscience, Inc., 311 Ferst Drive NW, Ste. L1325A, Atlanta, Georgia 30332, United States., Petros JA; Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, United States., Kobayashi T; Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School & Massachusetts General Hospital, Boston, Massachusetts 02114, United States., Duda DG; Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School & Massachusetts General Hospital, Boston, Massachusetts 02114, United States., Oyelere AK; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States.; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Sep 05; Vol. 7 (10), pp. 3155-3169. Date of Electronic Publication: 2024 Sep 05 (Print Publication: 2024).
DOI:	10.1021/acsptsci.4c00358
Abstrakt:	Hepatocellular carcinoma (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylase (HDAC) 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. Competing Interests: The authors declare the following competing financial interest(s): Conflicts of Interest: A.K.O. is the founder of Sophia Bioscience, Inc. S.T. is the PI on 1R43CA224642, an NIH/NCI SBIR grant that funded part of this study at Sophia Bioscience, Inc. D.A.G. is interim CEO of Sophia Bioscience, Inc. J.A.P. is the sub-contract PI on 1R43CA224642. A.K.O. received consultant fees from Sophia Bioscience while D.G.D. received consultant fees from Innocoll Pharmaceuticals and research grants from Exelixis, Bayer, BMS, and Surface Oncology. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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