Experimental evolution of an oncolytic vesicular stomatitis virus with increased selectivity for p53-deficient cells

Area of Science:

• Oncolytic virotherapy
• Molecular biology
• Cancer research

Background:

• Experimental evolution is a powerful tool for biotechnological applications.
• Oncolytic virotherapy utilizes viruses to selectively target and destroy cancer cells.
• The tumor suppressor gene p53 is frequently inactivated in human cancers.

Purpose of the Study:

• To adapt a rapidly evolving RNA virus, vesicular stomatitis virus (VSV), to cancer cells with deficient p53.
• To investigate the potential of experimental evolution for enhancing oncolytic virus efficacy against p53-inactivated tumors.

Main Methods:

• Established four independent evolution lines of VSV in p53-knockout mouse embryonic fibroblasts (p53-/- MEFs).
• Assessed viral fitness and cytotoxicity in p53-/- and isogenic p53+/+ cells.
• Performed half-maximal effective dose (EC50) assays in p53-positive (CT26) and p53-deficient (4T1) cancer cell lines.
• Evaluated in vivo efficacy using 4T1 syngeneic tumor models in mice.

Main Results:

• Some evolved VSV lines exhibited increased fitness and cytotoxicity specifically in p53-/- cells.
• Evolved viruses showed greater efficacy against p53-deficient 4T1 breast cancer cells compared to parental VSV.
• One evolved VSV line significantly delayed tumor growth and induced transient suppression in 4T1 tumor models.
• Full-length sequencing did not reveal obvious genetic changes associated with the observed adaptation.

Conclusions:

• RNA viruses can be specifically adapted to cancer features like p53 inactivation.
• Experimental evolution is a valuable strategy for developing targeted oncolytic virotherapies.
• Adaptation to p53 deficiency can enhance viral oncolytic activity and therapeutic potential.