title: Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies.
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.
authors.affiliation: Gene Therapy and Cancer, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036 Barcelona, Spain.
authors.forename: Eneko
authors.initials: E
authors.lastname: Villanueva
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Dr Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Pilar
authors.identifier: 0000-0003-4314-4584
authors.initials: P
authors.lastname: Navarro
authors.affiliation: Gene Therapy and Cancer, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036 Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08036 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Rovira-Rigau
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Annarita
authors.initials: A
authors.lastname: Sibilio
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Méndez
authors.affiliation: Gene Therapy and Cancer, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036 Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08036 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D026723:Polyadenylation; D014176:Protein Biosynthesis / Q000235:genetics*; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C554939:CPEB4 protein, human; D016601:RNA-Binding Proteins