p21 Promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

Area of Science:

• Oncolytic virotherapy
• Cancer biology
• Molecular oncology

Background:

• Oncolytic adenoviruses selectively target cancer cells with dysregulated Rb pathways, common in most human cancers.
• The adenovirus dl922-947 demonstrates potent oncolytic activity, exceeding wild-type and dl1520 (Onyx-015) in preclinical models.

Purpose of the Study:

• To identify host cell factors influencing the cytotoxicity of the oncolytic adenovirus dl922-947.
• To investigate the role of p21 in modulating dl922-947 efficacy in cancer cells.

Main Methods:

• Utilized isogenic cell lines (MRC5-VA vs. MRC5) and ovarian cancer cell lines (SKOV3ip1, TOV21G, A2780CP) to assess dl922-947 sensitivity.
• Employed microarray and western blot analyses to evaluate gene expression, including p21.
• Used siRNA to knockdown p21 in sensitive cells and assessed viral activity.
• Expressed p21 in resistant cells to determine its effect on viral activity in vitro and in vivo xenografts.

Main Results:

• Cellular sensitivity to dl922-947 correlated with G1/S checkpoint status and S-phase population, not solely infectivity or replication.
• p21 expression levels strongly correlated with dl922-947 cytotoxicity.
• p21 deficiency reduced viral efficacy, while p21 expression enhanced it in both sensitive and resistant cancer models.
• siRNA-mediated p21 knockdown decreased viral cytotoxicity, whereas p21 expression increased it.

Conclusions:

• Host cell factors, particularly p21 expression, significantly influence oncolytic adenovirus efficacy beyond infectivity.
• p21 plays a critical role in determining cancer cell susceptibility to dl922-947.
• p21 expression may serve as a predictive biomarker for patient response in clinical trials of oncolytic adenovirus therapy.