Artikel
Akt and mTOR signalling in WHO grade II and III meningiomas
Akt und mTOR Signaltransduktion in WHO Grad II und III Meningeomen
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Autoren
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Peter Baumgarten
- Universitätsklinikum der Goethe Universität Frankfurt am Main, Klinik und Poliklinik für Neurochirurgie, Frankfurt am Main, Deutschland
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Simon Bernatz
- Goethe Universität Frankfurt, Edinger Institut, Neuropathologie, Frankfurt, Deutschland
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Christian Senft
- Universitätsklinikum der Goethe Universität Frankfurt am Main, Klinik und Poliklinik für Neurochirurgie, Frankfurt am Main, Deutschland
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Volker Seifert
- Universitätsklinikum der Goethe Universität Frankfurt am Main, Klinik und Poliklinik für Neurochirurgie, Frankfurt am Main, Deutschland
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Marlies Wagner
- Universitätsklinikum der Goethe Universität Frankfurt, Neuroradiologie, Frankfurt am Main, Deutschland
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Joachim Steinbach
- Universitätsklinikum Frankfurt, Neuroonkologie, Frankfurt am Main, Deutschland
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Patrick N. Harter
- Goethe Universität Frankfurt, Edinger Institut, Neuropathologie, Frankfurt, Deutschland
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Michael Ronellenfitsch
- Universitätsklinikum Frankfurt, Neuroonkologie, Frankfurt am Main, Deutschland
| Veröffentlicht: | 8. Mai 2019 |
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Gliederung
Text
Objective: Surgical resection and radiotherapy are still the main pillars of meningioma treatment. WHO Grade I meningiomas are benign and complete resection can be curative. Complete resection for atypical (WHO°II) and malignant (WHO °III) meningiomas is frequently more difficult to achieve and adjuvant radiotherapy is considered in the case of incomplete resection or for WHO° III meningiomas. Nevertheless, higher grade meningiomas frequently recur. Patient condition, localization as well as previous radiation dosage can limit the established treatment options for patients with recurring disease. Therefore alternative pharmacological therapies are urgently needed. Therapies targeting central growth signals like the Akt and mammalian target of rapamycin (mTOR) signalling cascade are investigated as treatment options for a variety of cancers. The aim of this study was to assess Akt/mTOR signalling in WHO °II and °III meningiomas as a rationale for an anti-mTOR therapy.
Methods: A total of 232 specimens of 138 meningioma patients were investigated by immunohistochemistry for the Akt activity marker phosphorylated (P)-PRAS40 and the mTOR activity markers P-4EBP1 as well as P-ribosomal protein S6 (PRPS6). Recurrences were included as well. Further, we correlated signalling with proliferation, WHO Grade, brain invasion, subtype, progression free survival and overall survival.
Results: Akt signalling as indicated by P-PRAS40 was detectable in 7/128 WHO Grade II and 1/10 Grade III meningiomas. mTOR signalling as indicated by P-4EBP1 was detectable in 36/120 Grade II and 7/10 Grade III meningiomas. Phosphorylation of RPS6 at Ser235/236 and Ser240/244 as further mTORC1 activity markers were detectable in 39/118 and 1/9 (Ser235/236) as well as in 5/125 and 0/9 (Ser240/244) in WHO Grade II and -III meningiomas. At least one activity marker of mTORC1 signalling (P-4EBP1 and/or P-RPS6 regardless of the phosphorylation site) was detectable in 62/125 WHO Grade II and 8/10 WHO Grade III meningiomas. Only P-4EBP1 and total S6RP correlated with proliferation as indicated by Ki67 staining. For tumours with above median P-4EBP1 staining a trend towards shorter progression-free survival was detectable.
Conclusion: In conclusion, Akt and mTOR signalling are detectable by immunohistochemistry in a significant portion of higher grade meningiomas which could support a rationale for a targeted therapy in these subgroups.
