Targeting of P53-transcriptional dysfunction by conditionally replicating adenovirus is not limited by P53-homologues

Abstract

A hallmark of hepatocellular carcinomas is the loss of p53 or its transcriptional functions. In this study we describe the generation of the conditionally-replicating adenovirus Adp53sensor for the treatment of p53-dysfunctional HCC. p53-selective attenuation of viral replication was achieved by using p53-dependent expression of the transcriptional repressor GAL4-KRAB that was directed against the adenoviral E1A locus. Adp53sensor shows efficient replication in p53-dysfunctional, but not in p53-active cells. In p53-dysfunctional cells, p53-analogous transcriptional activity by other p53-family members was not sufficient to compromise replication of Adp53sensor. Furthermore RNAi experiments suggest that endogenous p73 is able to efficiently interfere with attenuated p53-dependent transcription for fine-tuning of the transcriptional response, but p73 is neither able to interfere with a fully-developed p53-transcriptional response nor capable to significantly induce the p53-depedent promoter in Adp53sensor under conditions of p53-dysfunction. In comparison with a genetically similar, but p53-insensitive virus, Adp53-sensor replication was strongly inhibited in the normal liver of p53-wt-mice, but not in p53-ko-mice thus confirming the correct function of the p53-dependent inhibitory loop. Adp53sensor showed efficient lytic and replicative properties in all cells with p53-dysfunction and successfully inhibited the growth of HCC xenotransplants. Intravenous injection of Adp53sensor lead to significantly reduced liver damage compared to the control virus. Adp53sensor provides a strategy that should be broadly applicable to other transcriptionally regulated DNA-viruses.