Targeting oncolytic adenoviral agents to the epidermal growth factor pathway with a secretory fusion molecule.
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.
Hemminki
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Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, 35294-3300, USA. akseli@uab.edu
Dmitriev
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Liu
B
B
Desmond
R A
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Alemany
R
R
Curiel
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DT
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors