Publicaciones científicas
The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models
Daniel de la Nava 1 2 3 , Iker Ausejo-Mauleon 1 2 3 , Virginia Laspidea 1 2 3 , Marisol Gonzalez-Huarriz 1 2 3 , Andrea Lacalle 1 2 3 , Noelia Casares 1 2 3 , Marta Zalacain 1 2 3 , Lucía Marrodan 1 2 3 , Marc García-Moure 1 2 3 4 , Maria C Ochoa 1 2 3 , Antonio Carlos Tallon-Cobos 1 2 , Reyes Hernandez-Osuna 1 2 3 , Javier Marco-Sanz 1 2 3 , Laasya Dhandapani 1 2 3 , Irati Hervás-Corpión 1 2 3 , Oren J Becher 5 , Javad Nazarian 6 7 8 , Sabine Mueller 8 9 , Timothy N Phoenix 10 , Jasper van der Lugt 11 , Mikel Hernaez 1 12 , Elizabeth Guruceaga 1 12 , Carl Koschmann 13 , Sriram Venneti 13 , Joshua E Allen 14 , Matthew D Dun 15 16 17 , Juan Fueyo 4 , Candelaria Gomez-Manzano 4 , Jaime Gallego Perez-Larraya 1 2 18 , Ana Patiño-García 1 2 3 , Sara Labiano 1 2 3 , Marta M Alonso 1 2 3
Background: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.
Methods: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq and multiplexed immunofluorescence staining.
Results: The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.
Conclusions: The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.
CITA DEL ARTÍCULO Neuro Oncol. 2024 Mar 30:noae066. doi: 10.1093/neuonc/noae066
