Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy.
Replicating adenoviruses may prove to be effective anticancer agents if they can be engineered to selectively destroy tumor cells. We have constructed a virus (01/PEME) containing a novel regulatory circuit in which p53-dependent expression of an antagonist of the E2F transcription factor inhibits viral replication in normal cells. In tumor cells, however, the combination of p53 pathway defects and deregulated E2F allows replication of 01/PEME at near wild-type levels. The re-engineered virus also showed significantly enhanced efficacy compared with extensively studied E1b-deleted viruses such as dl1520 in human xenograft tumor models.
Ramachandra
M
M
Canji, Inc. 3525 John Hopkins Court, San Diego, CA 92121, USA. murali.ramachandra@canji.com
Rahman
A
A
Zou
A
A
Vaillancourt
M
M
Howe
J A
JA
Antelman
D
D
Sugarman
B
B
Demers
G W
GW
Engler
H
H
Johnson
D
D
Shabram
P
P
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000235:genetics; D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000628:therapy*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017501:Adenovirus E1B Proteins; D017503:Adenovirus E3 Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C099609:adenovirus death protein, Adenovirus