Effect of ONC201 and its derivatives (ONC206 and ONC212) on glioma cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA412217 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We performed microarray analysis in order to evaluate the effect of ONC201 and its derivatives (ONC206 and ONC212) on gene expression in U87 glioma cells.
2018-09-25 | GSE104273 | GEO
Project description:We performed microarray analysis in order to evaluate the effect of ONC201 on gene expression in glioma cells (U87).
2019-09-18 | GSE103963 | GEO
Project description:Effect of TIC10/ONC201 on glioma cells
| PRJNA407791 | ENA
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:The small molecule ONC201 is toxic in vitro to multiple cell lines and primary tumor samples of mantle cell lymphoma (MCL) and acute myeloid leukemia, even ones with unfavorable genetic features (notably including TP53 inactivation) or acquired resistance to other agents. Because the mechanism of action in these malignant hematologic cells appeared to differ from that in solid tumors, we performed gene expression profiling (GEP) studies on MCL lines treated with ONC201 and other agents with known mechanisms of action. Treatment of JeKo-1 cells with 5 uM ONC201 showed consistent and progressive increases or decreases over time in two sets of genes: upregulated genes, which implicated an ER stress response and mTOR pathway inhibition, and downregulated genes, which implicated reduced proliferation. These implicated effects of ONC201 were validated by confirmatory experiments. Similar GEP changes were observed in ONC201-naive Z138 cells after 24 hr of ONC201 treatment, but were not seen in Z138 cells made ONC201-resistant by chronic exposure. Finally, the GEP effects of ONC201 in JeKo-1 cells were mimicked by the ER stress inducer tunicamycin, but not by the direct MTOR inhibition rapamycin, further confirming an ER stress response and suggesting that inhibition of the mTOR pathway was by an indirect mechanism. For each experiment, cells from a single stock culture of each cell line used were aliquoted into individual culture plate wells, establishing individual replicates, and drugs were added to start the experiment. Treated replicates were harvested after the times of treatment indicated, by pelleting cells, lysing pellets in TriZOL, and freezing TriZOL until RNA isolation. Untreated replicates, serving as controls, were either harvested at the beginning of the experiment or at later times, as specified below.
2016-02-20 | E-GEOD-68091 | biostudies-arrayexpress
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:Two experiments were performed with ONC201/TIC10 in human colon cancer cell lines. The first experiment is TIC10-induced transcriptional changes at 48hrs in HCT116 p53-null cells (10uM). The second experiment is RKO cells, with and without acquired resistance to ONC201, treated with with ONC201 (10uM) for 48 hrs. For the first experiment, six samples of HCT116 p53-null cells with TIC10 (10uM) or DMSO treatment. Three replicates each. For the second experiment, six samples of wild-type RKO cells with ONC201 (10uM) or DMSO treatment and the same treatments for RKO cells with acquired resistance to ONC201.
2016-06-01 | E-GEOD-72865 | biostudies-arrayexpress
Project description:Effect of S4 treatment on glioma cells
| PRJNA846297 | ENA
Project description:RNASeq results for HK-374 treated with DMSO, radiation, ONC201 or radiation plus ONC201
2020-07-08 | GSE153982 | GEO
Project description:The small molecule ONC201 is toxic in vitro to multiple cell lines and primary tumor samples of mantle cell lymphoma (MCL) and acute myeloid leukemia, even ones with unfavorable genetic features (notably including TP53 inactivation) or acquired resistance to other agents. Because the mechanism of action in these malignant hematologic cells appeared to differ from that in solid tumors, we performed gene expression profiling (GEP) studies on MCL lines treated with ONC201 and other agents with known mechanisms of action. Treatment of JeKo-1 cells with 5 uM ONC201 showed consistent and progressive increases or decreases over time in two sets of genes: upregulated genes, which implicated an ER stress response and mTOR pathway inhibition, and downregulated genes, which implicated reduced proliferation. These implicated effects of ONC201 were validated by confirmatory experiments. Similar GEP changes were observed in ONC201-naive Z138 cells after 24 hr of ONC201 treatment, but were not seen in Z138 cells made ONC201-resistant by chronic exposure. Finally, the GEP effects of ONC201 in JeKo-1 cells were mimicked by the ER stress inducer tunicamycin, but not by the direct MTOR inhibition rapamycin, further confirming an ER stress response and suggesting that inhibition of the mTOR pathway was by an indirect mechanism.
2016-02-20 | GSE68091 | GEO