Alexandra Russo, Claudia Paret, Francesca Alt, Jürgen Burhenne, Margaux Fresnais, Wolfgang Wagner, Martin Glaser, Hannah Bender, Sabrina Huprich, Patrick Nikolaus Harter, Katharina Johanna Filipski, Nadine Lehmann, Nora Backes, Lea Roth, Larissa Seidmann, Clemens Sommer, Marc Alexander Brockmann, Torsten Pietsch, Marie Astrid Neu, Arthur Wingerter, Jörg Faber
- 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.
MetadatenAuthor: | Alexandra Russo, Claudia Paret, Francesca Alt, Jürgen Burhenne, Margaux Fresnais, Wolfgang Wagner, Martin Glaser, Hannah Bender, Sabrina Huprich, Patrick Nikolaus HarterORCiDGND, Katharina Johanna FilipskiGND, Nadine Lehmann, Nora Backes, Lea Roth, Larissa Seidmann, Clemens Sommer, Marc Alexander Brockmann, Torsten Pietsch, Marie Astrid Neu, Arthur Wingerter, Jörg Faber |
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URN: | urn:nbn:de:hebis:30:3-529784 |
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DOI: | https://doi.org/10.3390/ijms20174267 |
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ISSN: | 1422-0067 |
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ISSN: | 1661-6596 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/31480400 |
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Parent Title (English): | International journal of molecular sciences |
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Publisher: | Molecular Diversity Preservation International |
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Place of publication: | Basel |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2019 |
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Date of first Publication: | 2019/08/30 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2020/03/02 |
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Tag: | ATO; IGF; NOTCH1; SHH; WNT; ceritinib |
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Volume: | 20 |
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Issue: | 17, Art. 4267 |
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Page Number: | 19 |
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First Page: | 1 |
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Last Page: | 19 |
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Note: | 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 |
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HeBIS-PPN: | 460970941 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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