Reversal gene expression assessment for drug repurposing, a case study of glioblastoma
Abstract Background Glioblastoma (GBM) is a rare brain cancer with an exceptionally high mortality rate, which illustrates the pressing demand for more effective therapeutic options. Despite considerable research efforts on GBM, its underlying biological mechanisms remain unclear. Furthermore, none...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-06046-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544341067137024 |
|---|---|
| author | Shixue Sun Zeenat Shyr Kathleen McDaniel Yuhong Fang Dingyin Tao Catherine Z. Chen Wei Zheng Qian Zhu |
| author_facet | Shixue Sun Zeenat Shyr Kathleen McDaniel Yuhong Fang Dingyin Tao Catherine Z. Chen Wei Zheng Qian Zhu |
| author_sort | Shixue Sun |
| collection | DOAJ |
| description | Abstract Background Glioblastoma (GBM) is a rare brain cancer with an exceptionally high mortality rate, which illustrates the pressing demand for more effective therapeutic options. Despite considerable research efforts on GBM, its underlying biological mechanisms remain unclear. Furthermore, none of the United States Food and Drug Administration (FDA) approved drugs used for GBM deliver satisfactory survival improvement. Methods This study presents a novel computational pipeline by utilizing gene expression data analysis for GBM for drug repurposing to address the challenges in rare disease drug development, particularly focusing on GBM. The GBM Gene Expression Profile (GGEP) was constructed with multi-omics data to identify drugs with reversal gene expression to GGEP from the Integrated Network-Based Cellular Signatures (iLINCS) database. Results We prioritized the candidates via hierarchical clustering of their expression signatures and quantification of their reversal strength by calculating two self-defined indices based on the GGEP genes’ log2 foldchange (LFC) that the drug candidates could induce. Among five prioritized candidates, in-vitro experiments validated Clofarabine and Ciclopirox as highly efficacious in selectively targeting GBM cancer cells. Conclusions The success of this study illustrated a promising avenue for accelerating drug development by uncovering underlying gene expression effect between drugs and diseases, which can be extended to other rare diseases and non-rare diseases. |
| format | Article |
| id | doaj-art-231cfc57cfae4854b7b861da8ffa99b3 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-231cfc57cfae4854b7b861da8ffa99b32025-01-12T12:37:48ZengBMCJournal of Translational Medicine1479-58762025-01-0123111810.1186/s12967-024-06046-1Reversal gene expression assessment for drug repurposing, a case study of glioblastomaShixue Sun0Zeenat Shyr1Kathleen McDaniel2Yuhong Fang3Dingyin Tao4Catherine Z. Chen5Wei Zheng6Qian Zhu7Informatics Core, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Early Translation Branch, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Early Translation Branch, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Analytical Chemistry Core, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Analytical Chemistry Core, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Early Translation Branch, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Early Translation Branch, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Informatics Core, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)Abstract Background Glioblastoma (GBM) is a rare brain cancer with an exceptionally high mortality rate, which illustrates the pressing demand for more effective therapeutic options. Despite considerable research efforts on GBM, its underlying biological mechanisms remain unclear. Furthermore, none of the United States Food and Drug Administration (FDA) approved drugs used for GBM deliver satisfactory survival improvement. Methods This study presents a novel computational pipeline by utilizing gene expression data analysis for GBM for drug repurposing to address the challenges in rare disease drug development, particularly focusing on GBM. The GBM Gene Expression Profile (GGEP) was constructed with multi-omics data to identify drugs with reversal gene expression to GGEP from the Integrated Network-Based Cellular Signatures (iLINCS) database. Results We prioritized the candidates via hierarchical clustering of their expression signatures and quantification of their reversal strength by calculating two self-defined indices based on the GGEP genes’ log2 foldchange (LFC) that the drug candidates could induce. Among five prioritized candidates, in-vitro experiments validated Clofarabine and Ciclopirox as highly efficacious in selectively targeting GBM cancer cells. Conclusions The success of this study illustrated a promising avenue for accelerating drug development by uncovering underlying gene expression effect between drugs and diseases, which can be extended to other rare diseases and non-rare diseases.https://doi.org/10.1186/s12967-024-06046-1Rare diseasesDrug repurposingGlioblastomaMulti-omics analysisReversal gene expression |
| spellingShingle | Shixue Sun Zeenat Shyr Kathleen McDaniel Yuhong Fang Dingyin Tao Catherine Z. Chen Wei Zheng Qian Zhu Reversal gene expression assessment for drug repurposing, a case study of glioblastoma Journal of Translational Medicine Rare diseases Drug repurposing Glioblastoma Multi-omics analysis Reversal gene expression |
| title | Reversal gene expression assessment for drug repurposing, a case study of glioblastoma |
| title_full | Reversal gene expression assessment for drug repurposing, a case study of glioblastoma |
| title_fullStr | Reversal gene expression assessment for drug repurposing, a case study of glioblastoma |
| title_full_unstemmed | Reversal gene expression assessment for drug repurposing, a case study of glioblastoma |
| title_short | Reversal gene expression assessment for drug repurposing, a case study of glioblastoma |
| title_sort | reversal gene expression assessment for drug repurposing a case study of glioblastoma |
| topic | Rare diseases Drug repurposing Glioblastoma Multi-omics analysis Reversal gene expression |
| url | https://doi.org/10.1186/s12967-024-06046-1 |
| work_keys_str_mv | AT shixuesun reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma AT zeenatshyr reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma AT kathleenmcdaniel reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma AT yuhongfang reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma AT dingyintao reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma AT catherinezchen reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma AT weizheng reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma AT qianzhu reversalgeneexpressionassessmentfordrugrepurposingacasestudyofglioblastoma |