Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies

Eneko Villanueva,Annarita Sibilio,Maria Rovira-Rigau,Raúl Méndez,Cristina Fillat,Pilar Navarro

doi:10.1038/ncomms14833

Abstract

Systemic treatment of cancer requires tumour-selective therapies that eliminate cancer cells yet preserve healthy tissues from undesired damage. Tumoral transformation is associated with profound effects in translational reprogramming of gene expression, such that tumour-specific translational regulation presents an attractive possibility for generating oncoselective therapies. We recently discovered that mRNA translational control by cytoplasmic polyadenylation element-binding proteins (CPEBs) is reactivated in cancer. Here we present a novel approach to restrict genetic-engineered therapies to malignant tissues based on CPEB translational regulation of target mRNAs. We demonstrate that tumour reprogramming of CPEB-mediated mRNA stability and translational regulation modulates tumour-specific expression of viral proteins. For oncolytic adenoviruses, insertion of CPE regulatory sequences in the 3′-untranslated region of the E1A gene provides oncoselectivity, with full potency in cancer cells but attenuated in normal tissues. Our results demonstrate the potential of this strategy to improve oncolytic virus design and provide a framework for exploiting CPE-regulated transgenes for therapy.

Highlights

Systemic treatment of cancer requires tumour-selective therapies that eliminate cancer cells yet preserve healthy tissues from undesired damage
These mRNAs were expressed in a battery of normal (HPDE) and tumour (RWP-1, PANC-1 and MIA PaCa-2) pancreatic cells expressing variable levels of CPEB1 and CPEB4 (Fig. 1a)
The second UTR was synthetized by combining cyclin B1 (cB1) cytoplasmic polyadenylation element (CPE) with an AU-rich elements (AREs) sequence that opposes CPE-mediated polyadenylation and translational activation from the tumour-necrosis factor-a (TNF-a) 30-untranslated region (30-UTRs) mRNA (TNF-a-cB1)

Summary

Introduction

Systemic treatment of cancer requires tumour-selective therapies that eliminate cancer cells yet preserve healthy tissues from undesired damage. Most efforts to achieve such selective control have been based on the use of tumour-specific promoters[1] and, more recently, by the engineering of target site-recognizing, tissue-specific microRNA (miRNA)[2,3,4,5,6] Both strategies contribute highly to tumour selectivity, it has become evident that the post-transcriptional regulation of specific mRNA subpopulations contributes substantially to the broad expression changes of genes responsible for the cancer phenotype[7]. We generated a modified adenovirus in which the E1A protein expression is regulated by CPEBs, to obtain oncoselectivity and attenuated toxicity in non-transformed tissues This novel targeting modality increases the therapeutic index of an oncolytic adenovirus and provides a new paradigm for its applicability to gene transfer-based therapeutic approaches

Methods

Results

Conclusion