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Targeting oncolytic adenoviral agents to the epidermal growth factor pathway with a secretory fusion molecule
A Hemminki1, I Dmitriev, B Liu
1Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, 35294-3300, USA. akseli@uab.edu
Abstract:
Cancer gene therapy with conditionally replicating adenoviruses is a powerful way of overcoming low tumor transduction. However, one of the main remaining obstacles is the highly variable level of the coxsackie-adenovirus receptor expression on human primary cancers. In contrast, the epidermal growth factor receptor (EGFR) is overexpressed in various tumor types, and its expression correlates with metastatic behavior and poor prognosis. We constructed an adenovirus expressing a secretory adaptor capable of retargeting adenovirus to EGFR, resulting in a more than 150-fold increase in gene transfer. A replication-competent dual-virus system secreting the adaptor displayed increased oncolytic potency in vitro and therapeutic gain in vivo. This approach could translate into increased efficacy and specificity in the treatment of EGFR overexpressing human cancers.
Insights
Researchers developed a novel gene therapy using adenoviruses retargeted to EGFR. This approach significantly enhances gene transfer and oncolytic potency, offering a promising strategy for EGFR-overexpressing cancers.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- Conditionally replicating adenoviruses show promise for cancer gene therapy by overcoming low tumor transduction.
- Variable coxsackie-adenovirus receptor (CAR) expression on human cancers limits adenovirus efficacy.
- Epidermal growth factor receptor (EGFR) is overexpressed in many tumors, correlating with poor prognosis.
Purpose of the Study:
- To engineer an adenovirus system for enhanced gene transfer and oncolytic potency in EGFR-overexpressing cancers.
- To overcome the limitation of variable CAR expression by retargeting adenoviruses to EGFR.
Main Methods:
- Constructed an adenovirus expressing a secretory adaptor to retarget adenovirus to EGFR.
- Developed a replication-competent dual-virus system secreting the adaptor.
- Evaluated gene transfer efficiency, in vitro oncolytic potency, and in vivo therapeutic efficacy.
Main Results:
- Achieved a >150-fold increase in gene transfer by retargeting adenovirus to EGFR.
- Demonstrated increased in vitro oncolytic potency with the dual-virus system.
- Showed therapeutic gain in vivo using the engineered adenovirus system.
Conclusions:
- Adenovirus retargeting to EGFR significantly enhances gene transfer efficiency.
- The developed dual-virus system offers improved oncolytic potency and therapeutic efficacy.
- This strategy holds potential for treating EGFR-overexpressing human cancers with increased specificity and efficacy.