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.
Highlights
Glioblastoma (GB) is an incurable brain cancer and the most common primary brain tumor in adults [33]
Nimotuzumab inhibits epidermal growth factor receptor (EGFR) downstream signaling To test whether nimotuzumab inhibited signaling from the EGFR-downstream kinases Akt and mTOR complex 1 (mTORC1) (Fig. 1a), we exposed human LNT-229 glioblastoma cells to nimotuzumab or the intracellular EGFR inhibitor PD153035 [11]
Phosphorylation of Proline rich Akt substrate of 40 kDa (PRAS40) and ribosomal protein S6 (RPS6) is only detectable in a small proportion of tumor cells and does not correlate with EGFR gene amplification For histological characterization of our cohort, we evaluated the extent of necrosis, P-PRAS40, P-RPS6 and hypoxia-inducible factor 1α (HIF-1α) in perinecrotic as well as in vital tumor areas
Summary
Glioblastoma (GB) is an incurable brain cancer and the most common primary brain tumor in adults [33]. It is noteworthy that the EGFRvIII mutation if present usually is only found in a fraction of tumor cells within a GB [54] and that even during the course of standard treatment EGFRvIII is frequently lost [53]. GB is characterized by marked hypoxic areas, with typical histological features of neoangiogenesis and necrosis in a diffusely infiltrating growing glial tumor [25]. These areas reflect the metabolically challenging microenvironment where nutrient and oxygen supply can frequently not match demand of the tumor cells. The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a major cellular regulator of adaptive programs to hypoxia and stabilization occurs when oxygen is low [42]
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