Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control

Abstract

Background-In view of the limited success of available treatment modalities for a wide array of cancer, alternative and complementary therapeutic strategies need to be developed. Virotherapy employing conditionally replicative adenoviruses (CRAds) represents a promising targeted intervention relevant to a wide array of neoplastic diseases. Critical to the realization of an acceptable therapeutic index using virotherapy in clinical trials is the achievement of oncolytic replication in tumor cells, while avoiding non-specific replication in normal tissues. In this report, we exploited cancer-specific control of mRNA translation initiation in order to achieve enhanced replicative specificity of CRAd virotherapy agents. Heretofore, the achievement of replicative specificity of CRAd agents has been accomplished either by viral genome deletions or incorporation of tumor selective promoters. In contrast, control of mRNA translation has not been exploited for the design of tumor specific replicating viruses to date. We show herein, the utility of a novel approach that combines both transcriptional and translational regulation strategies for the key goal of replicative specificity.

Generation of a Conditionally Replicating Adenovirus Based on Targeted Destruction of E1A mRNA by a Cell Type-Specific MicroRNA

“…For example, Rodriguez et al inserted a prostate-specific antigen gene enhancer element upstream of the E1A gene to restrict viral replication to prostate cancer cells (40). Recently, regulatory elements from prostaglandin-endoperoxide synthase-2 (2) and fibroblast growth factor-2 (43) have been employed to favor the stability and translation, respectively, of E1A mRNA in certain types of cancer cells.…”

A Potent Oncolytic Adenovirus Selectively Blocks the STAT3 Signaling Pathway and Potentiates Cisplatin Antitumor Activity in Ovarian Cancer

“…For example, virotherapy with conditionally replicating adenoviruses (CRAds) has been shown to be a promising intervention relevant to a wide array of neoplastic diseases (Stoff-Khalili et al, 2008). Adenoviruses have many advantages, including their ability to infect a wide variety of cells, their easy replication, and their relative safety.…”

Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice

“…This finding is consistent with other work demonstrating the ability to target cancer cells using FGF-2 deived 5 0 UTR in adenovirus system. 28 Prostate-specific PTEN À/À mice are transgenic models that develop prostate cancer with disease progression, which mimic that seen in patients. Several studies have demonstrated that deletion and/or mutation of the PTEN gene leads to upregulation of the AKT/mTOR pathway, which can lead to increased eIF4E expression.…”