PT  - JOURNAL ARTICLE
AU  - Pascual-Pasto, Guillem
AU  - Bazan-Peregrino, Miriam
AU  - Olaciregui, Nagore G.
AU  - Restrepo-Perdomo, Camilo A.
AU  - Mato-Berciano, Ana
AU  - Ottaviani, Daniela
AU  - Weber, Klaus
AU  - Correa, Genoveva
AU  - Paco, Sonia
AU  - Vila-Ubach, Monica
AU  - Cuadrado-Vilanova, Maria
AU  - Castillo-Ecija, Helena
AU  - Botteri, Gaia
AU  - Garcia-Gerique, Laura
AU  - Moreno-Gilabert, Helena
AU  - Gimenez-Alejandre, Marta
AU  - Alonso-Lopez, Patricia
AU  - Farrera-Sal, Marti
AU  - Torres-Manjon, Silvia
AU  - Ramos-Lozano, Dolores
AU  - Moreno, Rafael
AU  - Aerts, Isabelle
AU  - Doz, François
AU  - Cassoux, Nathalie
AU  - Chapeaublanc, Elodie
AU  - Torrebadell, Montserrat
AU  - Roldan, Monica
AU  - König, Andrés
AU  - Suñol, Mariona
AU  - Claverol, Joana
AU  - Lavarino, Cinzia
AU  - Carmen de, Torres
AU  - Fu, Ligia
AU  - Radvanyi, François
AU  - Munier, Francis L.
AU  - Catalá-Mora, Jaume
AU  - Mora, Jaume
AU  - Alemany, Ramón
AU  - Cascalló, Manel
AU  - Chantada, Guillermo L.
AU  - Carcaboso, Angel M.
TI  - Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01
AID  - 10.1126/scitranslmed.aat9321
DP  - 2019 Jan 23
TA  - Science Translational Medicine
PG  - eaat9321
VI  - 11
IP  - 476
4099  - http://stm.sciencemag.org/content/11/476/eaat9321.short
4100  - http://stm.sciencemag.org/content/11/476/eaat9321.full
AB  - Eyes afflicted by chemoresistant retinoblastoma may need to be surgically removed to prevent life-threatening metastasis. To develop alternative treatments for retinoblastoma, Pascual-Pasto et al. investigated the oncolytic adenovirus VCN-01, which targets cells with dysregulated RB1. They found that VCN-01 can lyse even chemoresistant patient samples in vitro and was effective in mouse xenograft models. VCN-01 was safe in mice and juvenile rabbits. Initial results from the first pediatric retinoblastoma patients treated with intravitreous VCN-01 showed viral replication in tumor cells and no systemic inflammation. These encouraging results support the development of this oncolytic virus to be used for retinoblastoma therapy.Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1. VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.