A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Hepatocellular cancer (HCC) progression is linked to histone deacetylase (HDAC) activation, leading to gene silencing.
• Standard HDAC inhibitors are less effective in solid tumors compared to lymphomas.
• Targeting HDACs offers a potential therapeutic strategy for HCC.

Approach:

• Discovered a new class of HDAC inhibitors (HDACi) with selective cytotoxicity against human HCC cells.
• Evaluated the lead compound STR-V-53 in preclinical HCC models, including safety and efficacy studies.
• Investigated combination therapies of STR-V-53 with sorafenib and anti-PD1 immunotherapy.

Key Points:

• STR-V-53 demonstrated selective toxicity towards HCC cells and a good safety profile in mice.
• STR-V-53 suppressed tumor growth in orthotopic HCC xenograft models.
• Combination of STR-V-53 with sorafenib enhanced anti-tumor efficacy.
• STR-V-53 plus anti-PD1 therapy improved the CD8+ to regulatory T-cell (Treg) ratio and survival in immunocompetent mice.
• Durable responses were observed in 40% of mice treated with STR-V-53 and anti-PD1 therapy.

Conclusions:

• The novel HDACi STR-V-53 is a promising agent for treating hepatocellular cancer.
• STR-V-53 can enhance responses when used in combination with standard therapies like sorafenib and immunotherapy.