Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity

Abstract

The human telomerase reverse transcriptase (hTERT) promoter is known to selectively drive transgene expression in many human cancer cells expressing hTERT, the catalytic component of the telomerase ribonucleoprotein complex. We have created a conditionally replicative adenovirus where the viral E1A gene, which is required for viral replication, is under the control of the hTERT promoter (AdhTERTp-E1A). In vitro studies with AdhTERTp-E1A virus on a variety of normal and tumor cell lines have shown that viral genome replication and productive infection is primarily restricted to telomerase-positive tumor cells. Lytic replication was not observed in normal primary fibroblast and epithelial cell lines tested. In vivo administration of the virus into nude mice bearing human liver or prostate tumor xenografts produced significant tumor reduction and, in some cases, resulted in complete tumor regression. AdhTERTp-E1A virus did not actively express E1A in normal mouse liver, in contrast to a control oncolytic vector in which the CMV promoter (AdCMVp-E1A) was driving the E1A gene. In addition, AdhTERTp-E1A virus produced no apparent toxicity to the liver in systemically injected mice. The hTERT promoter-driven oncolytic virus also produced significantly less toxicity to freshly cultured human hepatocytes. These studies demonstrate that an oncolytic virus driven by the telomerase promoter can be used to effectively kill a wide variety of cancer cell types and has the potential to treat primary and metastatic cancer of diverse origins.

Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter

“…However, the spectrum of regulatory sequences available for this approach is limited, and many promoters are leaky, resulting in the gradual͞temporal production of toxic products. The only verified promoter that functions selectively in a diverse cancer-cell-specific manner without having significant activity in normal cells, is the telomerase promoter, which is being extensively used to drive transgene expression to eradicate cancer cells (25)(26)(27). Our demonstration that the PEG-Prom displays similar robust cancer-specific expression now provides an additional reagent for developing cancer-specific gene therapy vectors with clear cancer therapeutic potential.…”

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

“…[28][29][30][31][32][33] Oncolytic adenoviruses utilizing the hTERT promoter to control Ad early region genes have also been previously described. [34][35][36] By using both the E2F-1 promoter and the hTERT promoter to control different early region genes in the same Ad vector, we have constructed an oncolytic Ad which is active in a broad panel of tumor types and is safe and effective when delivered systemically.…”

Oncolytic adenovirus that overproduces ADP and replicates selectively in tumors due to hTERT promoter-regulated E4 gene expression

“…Various nonreplicating Ad vectors applying the hTERT promoter to regulate anticancer therapeutic genes have been reported. [16][17][18][19][20][21] Several oncolytic Ad vectors in which the hTERT promoter regulates the expression of the E1A [22][23][24][25][26][27][28] or E4 29,30 genes have also been described.…”