TY  - JOUR
A1  - Russo, Alexandra
A1  - Paret, Claudia
A1  - Alt, Francesca
A1  - Burhenne, Jürgen
A1  - Fresnais, Margaux
A1  - Wagner, Wolfgang
A1  - Glaser, Martin
A1  - Bender, Hannah
A1  - Huprich, Sabrina
A1  - Harter, Patrick Nikolaus
A1  - Filipski, Katharina Johanna
A1  - Lehmann, Nadine
A1  - Backes, Nora
A1  - Roth, Lea
A1  - Seidmann, Larissa
A1  - Sommer, Clemens
A1  - Brockmann, Marc Alexander
A1  - Pietsch, Torsten
A1  - Neu, Marie Astrid
A1  - Wingerter, Arthur
A1  - Faber, Jörg
T1  - Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor
T2  - International journal of molecular sciences
N2  - The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
KW  - ATO
KW  - ceritinib
KW  - IGF
KW  - SHH
KW  - NOTCH1
KW  - WNT
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/52978
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-529784
SN  - 1422-0067
SN  - 1661-6596
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
VL  - 20
IS  - 17, Art. 4267
SP  - 1
EP  - 19
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -