Targeting cancer by transcriptional control in cancer gene therapy and viral oncolysis

Abstract

Cancer-specificity is the key requirement for a drug or treatment regimen to be effective against malignant disease--and has rarely been achieved adequately to date. Therefore, targeting strategies need to be implemented for future therapies to ensure efficient activity at the site of patients' tumors or metastases without causing intolerable side-effects. Gene therapy and viral oncolysis represent treatment modalities that offer unique opportunities for tumor targeting. This is because both the transfer of genes with anti-cancer activity and viral replication-induced cell killing, respectively, facilitate the incorporation of multiple mechanisms restricting their activity to cancer. To this end, cellular mechanisms of gene regulation have been successfully exploited to direct therapeutic gene expression and viral cell lysis to cancer cells. Here, transcriptional targeting has been the role model and most widely investigated. This approach exploits cellular gene regulatory elements that mediate cell type-specific transcription to restrict the expression of therapeutic genes or essential viral genes, ideally to cancer cells. In this review, we first discuss the rationale for such promoter targeting and its limitations. We then give an overview how tissue-/tumor-specific promoters are being identified and characterized. Strategies to apply and optimize such promoters for the engineering of targeted viral gene transfer vectors and oncolytic viruses-with respect to promoter size, selectivity and activity in the context of viral genomes-are described. Finally, we discuss in more detail individual examples for transcriptionally targeted virus drugs. First highlighting oncolytic viruses targeted by prostate-specific promoters and by the telomerase promoter as representatives of tissue-targeted and pan-cancer-specific virus drugs respectively, and secondly recent developments of the last two years.