Minimal RB-responsive E1A promoter modification to attain potency, selectivity, and transgene-arming capacity in oncolytic adenoviruses.
Oncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity. For this purpose, the genetic backbone in which the transgene is inserted should be optimized to render transgene expression compatible with the adenovirus replication cycle and to keep genome size within the encapsidation size limit. In order to design a potent and selective oncolytic adenovirus that keeps intact all the viral functions with minimal increase in genome size, we inserted palindromic E2F-binding sites into the endogenous E1A promoter. The insertion of these sites controlling E1A-Δ24 results in a low systemic toxicity profile in mice. Importantly, the E2F-binding sites also increased the cytotoxicity and the systemic antitumor activity relative to wild-type adenovirus in all cancer models tested. The low toxicity and the increased potency results in improved antitumor efficacy after systemic injection and increased survival of mice carrying tumors. Furthermore, the constrained genome size of this backbone allows an efficient and potent expression of transgenes, indicating that this virus holds promise for overcoming the limitations of oncolytic adenoviral therapy.
Rojas
Juan J
JJ
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
Guedan
Sonia
S
Searle
Peter F
PF
Martinez-Quintanilla
Jordi
J
Gil-Hoyos
Raúl
R
Alcayaga-Miranda
Francisca
F
Cascallo
Manel
M
Alemany
Ramon
R
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003588:Cytopathogenic Effect, Viral; D050687:E2F1 Transcription Factor / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D050504:Oncolytic Viruses / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016160:Retinoblastoma Protein / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019076:Transgenes / Q000502:physiology; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D050687:E2F1 Transcription Factor; D012333:RNA, Messenger; D016160:Retinoblastoma Protein
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