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Published on: October 26, 2018
Characterization of an Oncolytic Adenovirus Vector Constructed to Target the cMet Receptor
Hany I Sakr1, David T Coleman2, James A Cardelli2
1Department of Cellular Biology and Anatomy, LSU Health Shreveport, Shreveport, LA, USA; Gene Therapy Program, LSU Health Shreveport, Shreveport, LA, USA; Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.
Abstract:
The cMet receptor is a homodimer with tyrosine kinase activity. Upon stimulation with its ligand, hepatocyte growth factor (HGF), the receptor mediates wide physiologic actions. The HGF-cMet signaling pathway is dysregulated in many cancers, which makes cMet an important target for novel therapeutic interventions. Oncolytic adenoviruses (Ads) have been used for the past three decades as a promising therapeutic approach for a wide array of neoplastic diseases. To date, achieving cancer-specific replication of oncolytic Ads has been accomplished by either viral genome deletions or by incorporating tumor selective promoters. To achieve novel specificity of oncolytic Ad infection of cancer cells that overexpress cMet, we inserted the HGF NK2 sequence, corresponding to a competitive antagonist of HGF binding to the cMet receptor, into the Ad serotype 5 (Ad5) fiber gene. The resulting vector, Ad5-pIX-RFP-FF/NK2, was rescued, amplified in HEK293 cells, and characterized. Binding specificity and viral infectivity were tested in various cancer cell lines that express varying levels of cMet and hCAR (the Ad5 receptor). We found that Ad5-pIX-RFP-FF/NK2 demonstrated binding specificity to the cMet receptor. In addition, there was enhanced viral infectivity and virus replication compared with a non-targeted Ad vector. Although NK2 weakly induces cMet receptor activation, our results showed no receptor phosphorylation in the context of an oncolytic Ad virus. In summary, these results suggest that an oncolytic Ad retargeted to the cMet receptor is a promising vector for developing a novel cancer therapeutic agent.
Insights
Researchers engineered an oncolytic adenovirus (Ad) to target cancer cells overexpressing the cMet receptor. This novel Ad vector, retargeted using the HGF NK2 sequence, demonstrated specific binding and enhanced infectivity for cancer therapy.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- The cMet receptor tyrosine kinase pathway is crucial for normal physiology but frequently dysregulated in various cancers.
- Oncolytic adenoviruses (Ads) are engineered viruses used for cancer therapy, with specificity typically achieved through genetic modifications.
- Targeting cancer-specific receptors like cMet offers a potential strategy for enhancing oncolytic Ad efficacy and safety.
Purpose of the Study:
- To engineer a novel oncolytic adenovirus (Ad5) with retargeted specificity towards cancer cells overexpressing the cMet receptor.
- To evaluate the binding specificity, infectivity, and replication of the retargeted oncolytic Ad vector in cancer cell lines.
Main Methods:
- The HGF NK2 sequence, a cMet antagonist, was inserted into the Ad serotype 5 (Ad5) fiber gene to create the retargeted vector Ad5-pIX-RFP-FF/NK2.
- The vector was rescued, amplified, and characterized in HEK293 cells.
- Binding specificity and viral infectivity were assessed in cancer cell lines with varying cMet and hCAR expression levels.
Main Results:
- Ad5-pIX-RFP-FF/NK2 exhibited specific binding to the cMet receptor.
- The retargeted vector demonstrated enhanced viral infectivity and replication compared to a non-targeted Ad vector.
- No significant cMet receptor phosphorylation was observed, indicating NK2 did not induce substantial receptor activation in this context.
Conclusions:
- Retargeting oncolytic adenoviruses to the cMet receptor is a feasible strategy for achieving cancer-specific infection.
- The developed Ad5-pIX-RFP-FF/NK2 vector shows promise as a novel therapeutic agent for cMet-expressing cancers.
- This approach offers a new avenue for developing targeted oncolytic virotherapy.
