Targeting EBV-associated gastric cancer by lytic induction therapy with nanatinostat

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• Latent Epstein-Barr virus (EBV) infection is linked to various human cancers, including EBV-associated gastric cancer (EBVaGC).
• EBV-associated gastric cancer (EBVaGC) lacks specific precision therapeutic strategies despite being a distinct subtype.
• Lytic induction therapy targeting EBV presents a potential treatment avenue for virus-associated malignancies.

Purpose of the Study:

• To evaluate nanatinostat (NSTAT) efficacy in inducing EBV lytic reactivation in EBVaGC.
• To assess the therapeutic potential of NSTAT-based lytic induction therapy in preclinical EBVaGC models.
• To investigate the molecular mechanisms underlying NSTAT's action in EBVaGC cells.

Main Methods:

• In vitro and in vivo studies using two representative EBVaGC cell lines.
• Treatment with nanatinostat (NSTAT), a histone deacetylase (HDAC) inhibitor.
• Combination therapy with NSTAT and valganciclovir (GCV).
• Analysis of EBV gene expression (immediate-early, early, late genes).
• Assessment of global histone acetylation, c-MYC and BCL2 expression, cell cycle, and cell death.

Main Results:

• NSTAT efficiently induced EBV lytic gene expression in EBVaGC cells.
• NSTAT promoted global histone acetylation and suppressed c-MYC and BCL2.
• NSTAT treatment led to cell cycle arrest and cell death in EBVaGC cells.
• Combined NSTAT and GCV therapy demonstrated significant antitumor efficacy in vitro and in vivo.
• The combined therapy was found to be safe in preclinical models.

Conclusions:

• Nanatinostat (NSTAT) is effective in inducing EBV lytic reactivation in EBV-associated gastric cancer (EBVaGC).
• NSTAT-based lytic induction therapy, particularly in combination with valganciclovir (GCV), exhibits potent antitumor activity and safety.
• This study supports the potential of NSTAT and GCV as a precision therapeutic strategy for EBVaGC.