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Authors: Saeed, Mohamed E. M.
Kadioglu, Onat
Greten, Henry Johannes
Yildirim, Adem
Mayr, Katharina
Wenz, Frederik
Giordano, Frank
Efferth, Thomas
Title: Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma
Online publication date: 10-May-2021
Language: english
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.
DDC: 570 Biowissenschaften
570 Life sciences
610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
Document type specification: Scientific article
License: CC BY
Information on rights of use:
Journal: Investigational new drugs
Pages or article number: 670
Publisher: Springer Science + Business Media B.V.
Publisher place: Dordrecht u.a.
Issue date: 2021
ISSN: 1573-0646
Publisher URL:
Publisher DOI: 10.1007/s10637-020-01037-7
Appears in collections:JGU-Publikationen

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