An oncolytic adenovirus vector combining enhanced cell-to-cell spreading, mediated by the ADP cytolytic protein, with selective replication in cancer cells with deregulated wnt signaling.
We have constructed a novel oncolytic adenovirus (Ad) vector named VRX-009 that combines enhanced cell spread with tumor-specific replication. Enhanced spread, which could significantly increase antitumor efficacy, is mediated by overexpression of the Ad cytolytic protein named ADP (also known as E3-11.6K). Replication of VRX-009 is restricted to cells with a deregulated wnt signal transduction pathway by replacement of the wild-type Ad E4 promoter with a synthetic promoter consisting of five consensus binding sites for the T-cell factor transcription factor. Tumor-selective replication is indicated by several lines of evidence. VRX-009 expresses E4ORF3, a representative Ad E4 protein, only in colon cancer cell lines. Furthermore, VRX-009 replicates preferentially in colon cancer cell lines as evidenced by virus productivity 2 orders of magnitude higher in SW480 colon cancer cells than in A549 lung cancer cells. Replication in primary human bronchial epithelial cells and human umbilical vein endothelial cells was also significantly lower than in SW480 cells. When tested in human tumor xenografts in nude mice, VRX-009 effectively suppressed the growth of SW480 colon tumors but not of A549 lung tumors. VRX-009 may provide greater level of antitumor efficacy than standard oncolytic Ad vectors in tumors in which a defect in wnt signaling increases the level of nuclear beta-catenin.
Toth
Karoly
K
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63126, USA.
Djeha
Hakim
H
Ying
Baoling
B
Tollefson
Ann E
AE
Kuppuswamy
Mohan
M
Doronin
Konstantin
K
Krajcsi
Peter
P
Lipinski
Kai
K
Wrighton
Christopher J
CJ
Wold
William S M
WS
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017503:Adenovirus E3 Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017504:Adenovirus E4 Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D004730:Endothelium, Vascular / Q000378:metabolism / Q000821:virology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D010957:Plasmids / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D014779:Virus Replication; D051153:Wnt Proteins; D023041:Xenograft Model Antitumor Assays
D017503:Adenovirus E3 Proteins; D017504:Adenovirus E4 Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C099609:adenovirus death protein, Adenovirus