Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies

Eneko Villanueva, Pilar Navarro, Maria Rovira-Rigau, Annarita Sibilio, Raúl Méndez () and Cristina Fillat ()
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Eneko Villanueva: Gene Therapy and Cancer, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Pilar Navarro: Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute)
Maria Rovira-Rigau: Gene Therapy and Cancer, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Annarita Sibilio: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Raúl Méndez: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Cristina Fillat: Gene Therapy and Cancer, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14833

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