Liver cancer protease activity profiles support therapeutic options with matrix metalloproteinase-activatable...

Area of Science:

• Oncolytic virology
• Cancer therapy
• Biotechnology

Background:

• Liver cancers present significant therapeutic challenges with limited treatment options.
• Oncolytic viruses offer a promising approach but require targeted activation to minimize off-tumor effects.

Purpose of the Study:

• To develop an oncolytic measles virus (MV) engineered for preferential activation within liver tumor microenvironments.
• To enhance the safety profile of oncolytic virotherapy for primary and secondary liver malignancies.

Main Methods:

• Assessed protease activity (urokinase-type plasminogen activator and matrix metalloproteinase-2 [MMP-2]) in liver tumor versus nontumorous tissues.
• Engineered MV fusion protein variants with matrix metalloproteinase (MMP) substrate motifs at the protease cleavage site.
• Identified and validated the PQGLYA motif for efficient cleavage and viral activation.
• Generated and characterized the MMP-activatable oncolytic MV-MMPA1 virus.

Main Results:

• Significantly higher MMP-2 activity was observed in primary liver tumor tissues compared to adjacent healthy tissues.
• The MV-MMPA1 virus demonstrated efficient cleavage and syncytia formation on protease-positive tumor cells.
• MV-MMPA1 showed strong restriction in primary human hepatocytes and healthy liver tissue.
• The virus maintained efficacy comparable to the parental MV in liver tumor tissue sections.

Conclusions:

• The MMP activation strategy effectively creates tumor-specific oncolytic viruses.
• MV-MMPA1 represents a potentially safer and more effective oncolytic virus for treating liver cancers.
• This approach holds significant clinical promise for improving liver cancer therapy.