Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• Oncolytic virotherapy shows promise but faces challenges in clinical efficacy.
• Hepatocellular carcinoma (HCC) remains a significant health concern with limited treatment options.

Purpose of the Study:

• To identify compounds that enhance the efficacy of M1 oncolytic virus in HCC treatment.
• To investigate the therapeutic potential of combining VCP inhibition with oncolytic virotherapy for HCC.

Main Methods:

• Conducted an anticancer drug screen to find M1 virus sensitizers in HCC.
• Utilized in vitro and in vivo models of HCC, including mouse models and primary HCC tissues.
• Assessed the safety and tolerability of the combined therapy in nonhuman primates.

Main Results:

• Identified a valosin-containing protein (VCP) inhibitor as a potent sensitizer, increasing M1 virus potency up to 3600-fold.
• Demonstrated that VCP inhibitors cooperate with M1 virus to suppress the IRE1α-XBP1 pathway, inducing endoplasmic reticulum (ER) stress and apoptosis in HCC cells.
• Showed improved oncolytic efficacy of M1 virus in HCC models and primary tissues with VCP inhibition.
• Confirmed the combinatorial strategy was well-tolerated in nonhuman primates.

Conclusions:

• Combined VCP inhibition and M1 oncolytic virus therapy represents a promising strategy for HCC treatment.
• The synergistic effect is mediated by inducing irresolvable ER stress and promoting apoptosis in cancer cells.
• This approach warrants further clinical investigation for HCC patients.