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@ARTICLE{Alhalabi:169758,
author = {O. Alhalabi$^*$ and M. N. C. Fletcher$^*$ and T.
Hielscher$^*$ and T. Kessler$^*$ and T. Lokumcu$^*$ and U.
Baumgartner and E. Wittmann$^*$ and S. Schlue$^*$ and M.
Göttmann$^*$ and S. Rahman$^*$ and L. Hai$^*$ and L.
Hansen-Palmus$^*$ and L. Puccio$^*$ and I. Nakano and C.
Herold-Mende and B. W. Day and W. Wick$^*$ and F. Sahm and
E. Phillips$^*$ and V. Goidts$^*$},
title = {{A} novel patient stratification strategy to enhance the
therapeutic efficacy of dasatinib in glioblastoma.},
journal = {Neuro-Oncology},
volume = {24},
number = {1},
issn = {1523-5866},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {DKFZ-2021-01541},
pages = {39-51},
year = {2022},
note = {B067#LA:B067# / 2022 Jan 5;24(1):39-51 / Junior Research
Group Bioinformatics and Omics Data Analytics},
abstract = {Glioblastoma is the most common primary malignancy of the
central nervous system with dismal prognosis. Genomic
signatures classify isocitrate dehydrogenase 1
(IDH)-wildtype glioblastoma into three subtypes: proneural,
mesenchymal and classical. Dasatinib, an inhibitor of
proto-oncogene kinase Src (SRC), is one of many therapeutics
which, despite promising preclinical results, has failed to
improve overall survival in glioblastoma patients in
clinical trials. We examined whether glioblastoma subtypes
differ in their response to dasatinib and could hence be
evaluated for patient enrichment strategies in clinical
trials.We carried out in silico analyses on glioblastoma
gene expression (TCGA) and single-cell RNA-Seq data. In
addition, in vitro experiments using glioblastoma stem-like
cells (GSCs) derived from primary patient tumors were
performed, with complementary gene expression profiling and
immunohistochemistry analysis of tumor samples.Patients with
the mesenchymal subtype of glioblastoma showed higher SRC
pathway activation based on gene expression profiling.
Accordingly, mesenchymal GSCs were more sensitive to SRC
inhibition by dasatinib compared to proneural and classical
GSCs. Notably, SRC phosphorylation status did not predict
response to dasatinib treatment. Furthermore, serpin
peptidase inhibitor clade H member 1 (SERPINH1), a collagen
related heat-shock protein associated with cancer
progression, was shown to correlate with dasatinib response
and with the mesenchymal subtype.This work highlights
further molecular-based patient selection strategies in
clinical trials and suggests the mesenchymal subtype as well
as SERPINH1 to be associated with response to dasatinib. Our
findings indicate that stratification based on gene
expression subtyping should be considered in future
dasatinib trials.},
keywords = {Dasatinib (Other) / Glioblastoma (Other) / Glioblastoma
stem-like cells (Other) / SERPINH1 (Other) / SRC (Other)},
cin = {B067 / B060 / C060 / B320},
ddc = {610},
cid = {I:(DE-He78)B067-20160331 / I:(DE-He78)B060-20160331 /
I:(DE-He78)C060-20160331 / I:(DE-He78)B320-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34232320},
doi = {10.1093/neuonc/noab158},
url = {https://inrepo02.dkfz.de/record/169758},
}