Oncolytic Viruses Driven by Tumor-Specific Promoters

Abstract

Oncolytic viruses can selectively replicate in and lead to tumor cell lysis with minimal infection/replication potential in adjoining non-neoplastic tissue. Because of paramount safety concerns, first-generation oncolytic viruses were designed to be significantly attenuated in their lytic potential. Results from recent clinical trials have revealed the safety of this approach, but have underscored the urgency for design and testing of more tumor-selective and -potent viruses to realize the full therapeutic potential of this revolutionary treatment modality. With the discovery of various molecular/genetic changes associated with neoplasia, tumor-specific transcriptional targeting of viral virulence is being tapped to generate tumor- and tissue-specific variants. This review will focus on the various strategies exploited to generate viruses whose virulence is governed by tumor-specific transcriptional events.

Anticancer Gene Transfer for Cancer Gene Therapy

“…Adenoviruses enters the cells through endocytosis (Meier and Greber, 2003) after the binding of the fiber knob of the proteins on the viral capsid to the Coxsackie-Adenovirus-Receptor (CAR) on the cell surface. Subsequently it gets internalized through clathrin pits via interaction of integrins on the host cell with the RGD motif on the virus (Hardcastle et al, 2007). HSV based oncolytics use a different set of receptors (Spear, 2004) for viral entry.…”

“…These new studies utilized tumor-specific promoters in order to increase efficacy and specificity since the viruses are only able to replicate and lyse specifically in a tumor environment. Tumor epitopes are currently being used as targets of newly engineered viruses that initiated a revolution in tumor tropism (Hardcastle et al, 2007;Waehler et al, 2007). A new era for the virotherapy research begun when scientists realized that apart from the lytic potential, viruses could be used as gene delivery vehicles.…”

Selective Modification of Adenovirus Replication Can Be Achieved through Rational Mutagenesis of the Adenovirus Type 5 DNA Polymerase

“…Actively dividing tumor cells can contain between 10-and 30-times-higher dNTP concentrations than primary cells (16), providing a biochemical basis on which it might be possible to develop viral vectors that can selectively replicate in tumor cells but not normal cells. Since adenovirus vectors have been well studied as candidate oncolytic agents (8,9,11,14,19), we decided to focus our analysis on this virus and to determine the feasibility of generating modified adenoviruses containing mutated DNA polymerases with reduced dNTP binding affinities.The adenovirus DNA polymerase (AdPol) has been identified as a 140-kDa DNA polymerase of the alpha-like, Pol B family of polymerases (6, 12). Such polymerases contain several conserved motifs that are essential for polymerase function and contain amino acid residues that are necessary for dNTP binding (2, 29, 33), template DNA binding (4, 7, 15), and polymerase activity (5,23,30).…”

“…Actively dividing tumor cells can contain between 10-and 30-times-higher dNTP concentrations than primary cells (16), providing a biochemical basis on which it might be possible to develop viral vectors that can selectively replicate in tumor cells but not normal cells. Since adenovirus vectors have been well studied as candidate oncolytic agents (8,9,11,14,19), we decided to focus our analysis on this virus and to determine the feasibility of generating modified adenoviruses containing mutated DNA polymerases with reduced dNTP binding affinities.…”

Use of the Rad51 promoter for targeted anti-cancer therapy

“…Transcriptionally targeted anticancer therapy employs an elegant approach to selectively destroy cancer cells by placing a reporter and/or cytotoxic gene/oncolytic virus under the transcriptional control of the cancer or tissue-specific promoters (reviewed in refs. [21][22][23][24]. Examples of promoters that have been used in previous studies include the telomerase RNA subunit hTER and catalytic subunit hTERT (25)(26)(27)(28)(29)(30), tyrosinase (31), prostate antigen (32), survivin (33), and midkine genes (34).…”