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Omics-Based Drug Repurposing Approach: Integrated Omics Analysis Unveils the Efficacy of FDA-Approved Drug Belumosudil for Treatment of High-Grade Meningiomas
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(S 01): S1-S16
DOI: DOI: 10.1055/s-0044-1788212
*Corresponding author: (e-mail: sanjeeva@iitb.ac.in).
Abstract
Background: The high-grade meningiomas are a subset of most prevalent brain tumors that are difficult to treat with chemotherapeutics with reports of chemoresistance. We have performed an omics-driven drug repurposing approach; identifying key modulators involved in meningioma tumorigenesis and targeting them with known FDA-approved drugs.
Materials and Methods: Meta-omics analysis revealed the key targets involved in meningioma tumorigenesis. We identified an FDA-approved drug through drug docking and prepared a drug library incorporated as BDDF in BrainProt. Further, it was treated on high-grade meningioma cell line and cell-based assays and multi-omics analysis helped in understanding its efficacy.
Results: Integrated meta-omics analysis disclosed focal adhesion and integrins to be a key driver involving tumorigenesis. Belumosudil is a potent ROCK inhibitor found to be inhibiting ILK through in-silico-based methods. Further, protein–chemical interaction network revealed an association between ILK and ROCK providing a hint of Belumosudil to be effective. In vitro treatment of Belumosudil in the high-grade meningioma cell line showed an apoptotic effect with cell proliferation assay showing an IC50 of around 25 µM. Further global proteomics and metabolomics revealed enhanced oxidative phosphorylation and ROS-mediated cell death. An increase in intracellular ROS was further supported by FACS-based assay.
Conclusion: Among the kinase inhibitors, Belumosudil showed a strong interaction in in-silico-based assays. Further, in vitro treatment and cell-based assays show a promise for treatment against high-grade meningiomas. Further assays on patient-derived cell lines and animal-based studies shall consolidate our findings.
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
*Corresponding author: (e-mail: sanjeeva@iitb.ac.in).
Abstract
Background: The high-grade meningiomas are a subset of most prevalent brain tumors that are difficult to treat with chemotherapeutics with reports of chemoresistance. We have performed an omics-driven drug repurposing approach; identifying key modulators involved in meningioma tumorigenesis and targeting them with known FDA-approved drugs.
Materials and Methods: Meta-omics analysis revealed the key targets involved in meningioma tumorigenesis. We identified an FDA-approved drug through drug docking and prepared a drug library incorporated as BDDF in BrainProt. Further, it was treated on high-grade meningioma cell line and cell-based assays and multi-omics analysis helped in understanding its efficacy.
Results: Integrated meta-omics analysis disclosed focal adhesion and integrins to be a key driver involving tumorigenesis. Belumosudil is a potent ROCK inhibitor found to be inhibiting ILK through in-silico-based methods. Further, protein–chemical interaction network revealed an association between ILK and ROCK providing a hint of Belumosudil to be effective. In vitro treatment of Belumosudil in the high-grade meningioma cell line showed an apoptotic effect with cell proliferation assay showing an IC50 of around 25 µM. Further global proteomics and metabolomics revealed enhanced oxidative phosphorylation and ROS-mediated cell death. An increase in intracellular ROS was further supported by FACS-based assay.
Conclusion: Among the kinase inhibitors, Belumosudil showed a strong interaction in in-silico-based assays. Further, in vitro treatment and cell-based assays show a promise for treatment against high-grade meningiomas. Further assays on patient-derived cell lines and animal-based studies shall consolidate our findings.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India