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

Area of Science:

• Oncology
• Epigenetics
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) progression is linked to histone hypoacetylation driven by histone deacetylase (HDAC) activation.
• Histone deacetylase inhibitors (HDACi) are effective in lymphomas but show limited success in solid tumors like HCC.
• There is a need for targeted therapies that can overcome resistance in HCC treatment.

Purpose of the Study:

• To discover and characterize novel HDAC inhibitors with selective activity against HCC.
• To evaluate the efficacy of the lead compound STR-V-53 as a monotherapy and in combination with existing HCC treatments.
• To elucidate the mechanisms by which STR-V-53 impacts HCC cells and the tumor microenvironment.

Main Methods:

• Screening of a novel class of HDAC inhibitors for selective cytotoxicity against human HCC cells.
• In vivo efficacy studies using orthotopic xenograft and immunocompetent mouse models of HCC.
• Combination therapy studies with sorafenib and anti-PD1 immunotherapy.
• Transcriptomic analysis to understand the molecular mechanisms of STR-V-53 action.

Main Results:

• The lead compound STR-V-53 demonstrated exquisite selective cytotoxicity against HCC cells and a favorable safety profile in mice.
• STR-V-53 suppressed tumor growth in HCC xenograft models and showed enhanced efficacy when combined with sorafenib.
• Combination therapy with STR-V-53 and anti-PD1 immunotherapy increased the CD8+/Treg ratio, improved survival, and yielded durable responses in 40% of immunocompetent mice.
• Transcriptomic analysis revealed STR-V-53 primes HCC cells for immunotherapy by inhibiting HDACs, impairing glucose metabolism and DNA synthesis, upregulating apoptosis, and stimulating immune response pathways.

Conclusions:

• STR-V-53 is a novel and potent HDAC inhibitor with significant preclinical activity against HCC.
• STR-V-53 demonstrates potential as a combination therapy agent, enhancing the efficacy of both chemotherapy (sorafenib) and immunotherapy (anti-PD1).
• STR-V-53 primes HCC cells for immunotherapy, offering a promising new strategy for treating advanced liver cancer.