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

Michael W. Ronellenfitsch, Pia S. Zeiner, Michel Mittelbronn, Hans Urban, Torsten Pietsch, Dirk Reuter, Christian Senft, Joachim P. Steinbach, Manfred Westphal, Patrick N. Harter

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)81
Number of pages1
JournalActa neuropathologica communications
Volume6
Issue number1
DOIs
Publication statusPublished - 21 Aug 2018
Externally publishedYes

Keywords

  • Biomarker
  • Epidermal growth factor receptor
  • Glioblastoma
  • Mammalian target of rapamycin
  • Nimotuzumab
  • Targeted therapy

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