Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification
Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are ur...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/4/1219 |
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| author | Aideen C. Roddy Caitríona E. McInerney Tom Flannery Estelle G. Healy James P. Stewart Veronica J. Spence Jamie Walsh Manuel Salto-Tellez Darragh G. McArt Kevin M. Prise |
| author_facet | Aideen C. Roddy Caitríona E. McInerney Tom Flannery Estelle G. Healy James P. Stewart Veronica J. Spence Jamie Walsh Manuel Salto-Tellez Darragh G. McArt Kevin M. Prise |
| author_sort | Aideen C. Roddy |
| collection | DOAJ |
| description | Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM. |
| first_indexed | 2024-03-11T05:13:34Z |
| format | Article |
| id | doaj.art-f0c8e8ffdc1141a29cf7ee38fcb6596a |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T05:13:34Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-f0c8e8ffdc1141a29cf7ee38fcb6596a2023-11-17T18:28:12ZengMDPI AGBiomedicines2227-90592023-04-01114121910.3390/biomedicines11041219Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug IdentificationAideen C. Roddy0Caitríona E. McInerney1Tom Flannery2Estelle G. Healy3James P. Stewart4Veronica J. Spence5Jamie Walsh6Manuel Salto-Tellez7Darragh G. McArt8Kevin M. Prise9Patrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKPatrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKDepartment of Neurosurgery, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast BT12 6BA, UKRegional Service for Neuropathology, Institute of Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast BT12 6BA, UKPatrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKPatrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKPatrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKPatrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKPatrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKPatrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UKGlioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM.https://www.mdpi.com/2227-9059/11/4/1219brain tumorrecurrent glioblastomapatient-matched sampleswhole transcriptome profilingClariom<sup>TM</sup> D Human Assayconnectivity mapping |
| spellingShingle | Aideen C. Roddy Caitríona E. McInerney Tom Flannery Estelle G. Healy James P. Stewart Veronica J. Spence Jamie Walsh Manuel Salto-Tellez Darragh G. McArt Kevin M. Prise Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification Biomedicines brain tumor recurrent glioblastoma patient-matched samples whole transcriptome profiling Clariom<sup>TM</sup> D Human Assay connectivity mapping |
| title | Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification |
| title_full | Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification |
| title_fullStr | Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification |
| title_full_unstemmed | Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification |
| title_short | Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification |
| title_sort | transcriptional profiling of a patient matched cohort of glioblastoma idh wildtype for therapeutic target and repurposing drug identification |
| topic | brain tumor recurrent glioblastoma patient-matched samples whole transcriptome profiling Clariom<sup>TM</sup> D Human Assay connectivity mapping |
| url | https://www.mdpi.com/2227-9059/11/4/1219 |
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