Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Mohamed EM Saeed
- Onat Kadioglu
- Henry Johannes Greten
- Adem Yildirim
- Katharina Mayr
- Frederik Wenz
- Frank A Giordano
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000598067400001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1007/s10637-020-01037-7
- eISSN
- 1573-0646
- Externe Identifier
- Clarivate Analytics Document Solution ID: RR7ED
- PubMed Identifier: 33313992
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- INVESTIGATIONAL NEW DRUGS
- Schlüsselwörter
- Drug repurposing
- Precision medicine
- Targeted chemotherapy
- Virtual drug screening
- Paginierung
- 670 - 685
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma
- Sub types
- Article
- Ausgabe der Zeitschrift
- 39
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:title>Summary</jats:title><jats:p><jats:italic>Background</jats:italic> Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. <jats:italic>Methods</jats:italic> The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. <jats:italic>Results</jats:italic> Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. <jats:italic>Conclusions</jats:italic> In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.</jats:p>
- Autoren
- Mohamed EM Saeed
- Onat Kadioglu
- Henry Johannes Greten
- Adem Yildirim
- Katharina Mayr
- Frederik Wenz
- Frank A Giordano
- Thomas Efferth
- DOI
- 10.1007/s10637-020-01037-7
- eISSN
- 1573-0646
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- Investigational New Drugs
- Sprache
- en
- Online publication date
- 2020
- Paginierung
- 670 - 685
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1007/s10637-020-01037-7
- Datum der Datenerfassung
- 2023
- Titel
- Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma
- Ausgabe der Zeitschrift
- 39
Data source: Crossref
- Abstract
- Background Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 5512, Mainz, Germany.
- Autoren
- Mohamed EM Saeed
- Onat Kadioglu
- Henry Johannes Greten
- Adem Yildirim
- Katharina Mayr
- Frederik Wenz
- Frank A Giordano
- Thomas Efferth
- DOI
- 10.1007/s10637-020-01037-7
- eISSN
- 1573-0646
- Externe Identifier
- PubMed Identifier: 33313992
- PubMed Central ID: PMC8068653
- Funding acknowledgements
- Johannes Gutenberg-Universität Mainz:
- Open access
- true
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- Investigational new drugs
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Glioblastoma
- Brain Neoplasms
- Anthracyclines
- Proto-Oncogene Proteins B-raf
- Antineoplastic Agents
- Genotype
- Mutation
- Aged
- Drug Repositioning
- Class Ia Phosphatidylinositol 3-Kinase
- Transcriptome
- Temozolomide
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2020
- Open access status
- Open Access
- Paginierung
- 670 - 685
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2020
- Titel
- Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Case Reports
- Ausgabe der Zeitschrift
- 39
Files
https://link.springer.com/content/pdf/10.1007/s10637-020-01037-7.pdf https://europepmc.org/articles/PMC8068653?pdf=render
Data source: Europe PubMed Central
- Abstract
- Background Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.
- Date of acceptance
- 2020
- Autoren
- Mohamed EM Saeed
- Onat Kadioglu
- Henry Johannes Greten
- Adem Yildirim
- Katharina Mayr
- Frederik Wenz
- Frank A Giordano
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/33313992
- DOI
- 10.1007/s10637-020-01037-7
- eISSN
- 1573-0646
- Externe Identifier
- PubMed Central ID: PMC8068653
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- Invest New Drugs
- Schlüsselwörter
- Drug repurposing
- Precision medicine
- Targeted chemotherapy
- Virtual drug screening
- Aged
- Anthracyclines
- Antineoplastic Agents
- Brain Neoplasms
- Cell Line, Tumor
- Class Ia Phosphatidylinositol 3-Kinase
- Drug Repositioning
- Genotype
- Glioblastoma
- Humans
- Mutation
- Proto-Oncogene Proteins B-raf
- Temozolomide
- Transcriptome
- Sprache
- eng
- Country
- United States
- Paginierung
- 670 - 685
- PII
- 10.1007/s10637-020-01037-7
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma.
- Sub types
- Case Reports
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 39
Data source: PubMed
- Author's licence
- CC-BY
- Autoren
- Mohamed EM Saeed
- Onat Kadioglu
- Henry Johannes Greten
- Adem Yildirim
- Katharina Mayr
- Frederik Wenz
- Frank Giordano
- Thomas Efferth
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- JGU-Publikationen
- Resource version
- Published version
- DOI
- 10.1007/s10637-020-01037-7
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 1573-0646
- Zeitschrift
- Investigational new drugs
- Schlüsselwörter
- 570 Biowissenschaften
- 570 Life sciences
- 610 Medizin
- 610 Medical sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- 670 - 685
- Datum der Veröffentlichung
- 2021
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/5816
- Herausgeber
- Springer Science + Business Media B.V.
- Herausgeber URL
- https://doi.org/10.1007/s10637-020-01037-7
- Datum der Datenerfassung
- 2021
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Zugang
- Public
- Titel
- Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma
- Ausgabe der Zeitschrift
- 39
Files
saeed_mohamed_e._m.-drug_repurposi-20210510114527807.pdf
Data source: OPENSCIENCE.UB
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