The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models [RNA-seqII]
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PROVIDER: PRJNA1077327 | ENA |
REPOSITORIES: ENA
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Project description:Background: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs) are aggressive pediatric tumors harboring one of the poorest prognoses. Previous preclinical and clinical studies have demonstrated that oncolytic adenovirus Delta-24-RGD and the imipridone ONC201 are two promising therapies for these type of tumors as single agents. However, the combination of both agents has not been previously evaluated. Methods: Potential negative effects of ONC201 on the production of functional viruses were assessed by immunoblotting and replication assays. Antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, mTORC1 pathway analysis, Seahorse Stress Test, mitochondrial DNA content, and pH2A.X immunofluorescence were used to perform mechanistical studies. Models of both diseases were used to assess the efficacy of the combination in vivo. Tumor immune microenvironment was evaluated using flow cytometry. Results: ONC201 cotreatment with Delta-24-RGD did not affect the virus replication capability in human and murine pHGG and DMG models in vitro. Cytotoxicity analysis showed that cotreatment was either synergistic or additive. Mechanistically, combination treatment produces an increase of nuclear DNA damage and maintains the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extends the overall survival of mice implanted with human and murine pHGG and DMG cells, independently of H3 mutational status. Finally, combination treatment in murine DMG models revealed a proinflammatory phenotype reshaping of the tumor microenvironment. Conclusions: Delta-24-RGD/ONC201 combination improves the efficacy of each agent alone in vitro and in vivo models, maintaining transcriptional and phenotypical changes, producing exacerbated nuclear DNA damage, and leading to an augmented antitumor immune response.
2024-05-09 | GSE243223 | GEO
Project description: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.
2024-05-09 | GSE255971 | GEO
Project description:The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models
| PRJNA1077325 | ENA
Project description:Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to enhance tumor tropism and glioma-selective replication. E1A mutant adenovirus Delta-24-RGD has shown favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of intracellular and secreted glioma proteomes at late stage of Delta-24-RGD infection, when prominent autophagy has been described.
2018-12-11 | PXD010256 | Pride
Project description:Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to enhance tumor tropism and glioma-selective replication. E1A mutant adenovirus Delta-24-RGD has shown favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of intracellular and secreted glioma proteomes at late stage of Delta-24-RGD infection, when prominent autophagy has been described.
2018-12-11 | PXD011580 | Pride
Project description:Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to enhance tumor tropism and glioma-selective replication. E1A mutant adenovirus Delta-24-RGD has shown favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of cytosolic, nuclear, and secreted glioma proteomes throughout the early time course of Delta-24-RGD infection.
2018-10-22 | PXD008023 | Pride
Project description:The oncolytic adenovirus Delta-24-RGD in combination with ONC201 displays a potent antitumor effect in pediatric high-grade glioma models [RNA-seqI]
| PRJNA1017427 | ENA
Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.
2023-05-25 | PXD036245 | Pride
Project description:Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to enhance tumor tropism and glioma-selective replication. E1A mutant adenovirus Delta-24-RGD has shown favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of cytosolic, nuclear, and secreted glioma proteomes throughout the early time course of Delta-24-RGD infection.
2018-10-22 | PXD008022 | Pride
Project description:Although oncolytic adenoviruses have been widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains poorly studied. Here, we showed that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, Tα1 reprogrammed “M2-like” TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 was constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both in vitro and in vivo data showed that both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing new oncolytic engineered adenoviruses.
2024-06-28 | GSE271046 | GEO