The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models.

Autor:	de la Nava D; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Ausejo-Mauleon I; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Laspidea V; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Gonzalez-Huarriz M; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Lacalle A; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Casares N; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Zalacain M; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Marrodan L; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., García-Moure M; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Ochoa MC; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Tallon-Cobos AC; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Hernandez-Osuna R; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Marco-Sanz J; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Dhandapani L; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Hervás-Corpión I; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Becher OJ; Jack Martin Fund Division of Pediatric Hematology-oncology, Mount Sinai, New York, USA., Nazarian J; Division of Oncology and Children's Research Center, DIPG/DMG Research Center Zurich, University Children's Hospital Zurich, Zurich, Switzerland.; Virginia Tech University, Washington, District of Columbia, USA.; Children's National Health System, Center for Genetic Medicine Research, Washington, District of Columbia, USA., Mueller S; University of California, San Francisco San Francisco, California, USA.; Division of Oncology and Children's Research Center, DIPG/DMG Research Center Zurich, University Children's Hospital Zurich, Zurich, Switzerland., Phoenix TN; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA., van der Lugt J; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Hernaez M; Bioinformatics Platform, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Guruceaga E; Bioinformatics Platform, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Koschmann C; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA., Venneti S; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA., Allen JE; Chimerix, Inc. Durham, North Carolina, USA., Dun MD; Paediatric Stream, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine, and Wellbeing, Callaghan, New South Wales, Australia.; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia., Fueyo J; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Gomez-Manzano C; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Gallego Perez-Larraya J; Department of Neurology, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Patiño-García A; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Labiano S; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain., Alonso MM; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.; Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Spain.; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Aug 05; Vol. 26 (8), pp. 1509-1525.
DOI:	10.1093/neuonc/noae066
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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