Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector

Abstract

Recent data suggest that many tumors, such as malignant gliomas, have disrupted pRB function, either because of RB-1 gene mutations or as a result of mutations affecting upstream regulators of pRB such as cyclin D1 or p16/INK4a/MTS1 (ref. 1-5). Tumor suppression by pRB has been linked to its ability to repress E2F-responsive promoters such as the E2F-1 promoter. Thus, a prediction, which has not yet been demonstrated experimentally in vivo, is that E2F-responsive promoters should be more active in tumor cells relative to normal cells because of an excess of "free" E2F and loss of pRB/E2F repressor complexes. We demonstrate that adenoviral vectors that contain transgenes driven by the E2F-1 promoter can mediate tumor-selective gene expression in vivo, allowing for eradication of established gliomas with significantly less normal tissue toxicity than seen with standard adenoviral vectors. Our data indicate that de-repression of the E2F-1 promoter occurs in cancer cells in vivo, a finding that can be exploited to design viral vectors that mediate tumor-selective gene expression.

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

“…However, many aspects of the viral life cycle can be studied in mice. For example, the Ad E1A promoter 4 and the human E2F-1 promoter 48 are both active in mouse cells. As in humans, E1A produced by Ad can have toxic effects in mice, including the development of adenoviral nuclear inclusions.…”

Adenovirus-mediated transfer of Bax with caspase-8 controlled by myelin basic protein promoter exerts an enhanced cytotoxic effect in gliomas

“…MBP promoter 28 -30 and E2F-1 61 promoter have been reported to control the expression level of the transgenes in a glioma-specific manner. Several specific promoters to cancers such as ␣-fetoprotein (AFP) 62,63 and carcinoembryonic antigen 64,65 have been reported to be valuable, but the expression levels of these promoters are relatively low.…”

Noradrenaline transporter gene transfer for radiation cell kill by 131I meta-iodobenzylguanidine

“…This compound has similar uptake specificity to MIBG but much greater radiobiological effectiveness of cell killing. 24 A promising application of these tactics to glioma therapy, for example, could include virally mediated transfer of the NAT gene, under the control of a tumourspecific promoter (such as the E2F-1 promoter 25 ), followed by intra-cranial infusion of the ␣-emitting agent 211 At MABG. A suitable vector for such transfection may be a replication-compromised, variant herpes simplex virus whose safety has been demonstrated in a recent, Glasgow, phase 1, glioma therapy trial.…”