Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma

  • Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
Metadaten
Author:Michael Wilfried RonellenfitschORCiDGND, Pia Susan ZeinerORCiD, Michel Guy André Mittelbronn, Hans Urban, Torsten Pietsch, Dirk Reuter, Christian Alexander SenftORCiDGND, Joachim Peter SteinbachORCiDGND, Manfred Westphal, Patrick Nikolaus HarterORCiDGND
URN:urn:nbn:de:hebis:30:3-471507
DOI:https://doi.org/10.1186/s40478-018-0583-4
ISSN:2051-5960
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30129426
Parent Title (English):Acta Neuropathologica Communications
Publisher:Biomed Central
Place of publication:London
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/08/21
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/08/28
Tag:Biomarker; Epidermal growth factor receptor; Glioblastoma; Mammalian target of rapamycin; Nimotuzumab; Targeted therapy
Volume:6
Issue:1, Art. 81
Page Number:13
First Page:1
Last Page:13
Note:
Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
HeBIS-PPN:450930033
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0