Oncolytic adenovirus expressing a p53 variant resistant to degradation by HPV E6 protein exhibits potent and selective replication in cervical cancer.
Rationale in the development of novel treatment strategies for HPV-associated cancers is targeting on the basis of the presence of HPV in (pre)malignant cells. Here, we designed a new conditionally replicating adenovirus (CRAd) for selective and effective oncolytic replication in HPV-containing cells. As the backbone, we used the CRAd AdCB016, which replicates selectively in cells expressing HPV E6 and E7 proteins. To enhance its oncolytic potency, we armed AdCB016 with p53 variant mp53(268N), which is resistant to HPV E6-mediated degradation. The new CRAd AdCB016-mp53(268N) was analyzed for its lytic replication properties in cervical carcinoma cell lines, HPV-immortalized keratinocyte cell lines representing dysplastic cells, and primary human keratinocytes. AdCB016-mp53(268N) exhibited 10- to 1000-fold greater efficacy than AdCB016 on high-risk HPV-positive cervical carcinoma cells and HPV-immortalized keratinocytes. Importantly, infection with AdCB016-mp53(268N) did not affect primary nonmalignant human keratinocytes. This favorable efficacy and safety profile was confirmed in organotypic raft cultures. Our findings suggest that AdCB016-mp53(268N) is a promising new agent for treatment of HPV-associated human cancers.
Heideman
Daniëlle A M
DA
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. dam.heideman@vumc.nl
Steenbergen
Renske D M
RD
van der Torre
Jaco
J
Scheffner
Martin
M
Alemany
Ramon
R
Gerritsen
Winald R
WR
Meijer
Chris J L M
CJ
Snijders
Peter J F
PJ
van Beusechem
Victor W
VW
D000256:Adenoviridae / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D003124:Colorimetry; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D014644:Genetic Variation; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D050504:Oncolytic Viruses / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D011995:Recombination, Genetic; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy / Q000821:virology*
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53