Oncotarget

Research Papers:

Pasireotide is more effective than octreotide, alone or combined with everolimus on human meningioma in vitro

Thomas Graillon _, David Romano, Céline Defilles, Christophe Lisbonis, Alexandru Saveanu, Dominique Figarella-Branger, Pierre-Hugues Roche, Stéphane Fuentes, Olivier Chinot, Henry Dufour and Anne Barlier

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Oncotarget. 2017; 8:55361-55373. https://doi.org/10.18632/oncotarget.19517

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Abstract

Thomas Graillon1,2, David Romano1, Céline Defilles1, Christophe Lisbonis1, Alexandru Saveanu1,3, Dominique Figarella-Branger5,6, Pierre-Hugues Roche4, Stéphane Fuentes2, Olivier Chinot6,7, Henry Dufour1,2 and Anne Barlier1,3

1Aix Marseille Univ, CNRS CRN2M UMR7286, Marseille, France

2APHM, La Timone Hospital, Department of Neurosurgery, Marseille, France

3APHM, La Conception Hospital, Molecular Biology Laboratory, Marseille, France

4APHM, Nord Hospital, Department of Neurosurgery, Marseille, France

5APHM, La Timone Hospital, Department of Anatomopathology and Neuropathology, Marseille, France

6Aix Marseille Univ, INSERM, CRO2 UMR911, Marseille, France

7APHM, La Timone Hospital, Department of Neuro-oncology, Marseille, France

Correspondence to:

Thomas Graillon, email: [email protected], [email protected]

Keywords: meningioma, merlin, mTOR, pasireotide, somatostatin

Received: February 03, 2017     Accepted: July 12, 2017     Published: July 24, 2017

ABSTRACT

Pasireotide is a somatostatin analog (SSA) that targets somatostatin receptor subtype 1 (SST1), SST2, SST3, and SST5 with a high affinity. Pasireotide has a better antisecretory effect in acromegaly, Cushing’s disease, and neuroendocrine tumors than octreotide. In this study, we compared the effects of pasireotide to those of octreotide in vitro on meningioma primary cell cultures, both alone and in combination with the mTOR inhibitor everolimus. Significant mRNA expression levels of SST1, SST2, and SST5 were observed in 40.5%, 100%, and 35% of meningioma samples, respectively. Pasireotide had a significantly stronger inhibitory effect on cell proliferation than octreotide. The effect of pasireotide, but not of octreotide, was significantly stronger in the group expressing the highest level of SST1 mRNA. Combined treatment with pasireotide and everolimus induced a higher reduction in cell viability than that with octreotide plus everolimus. Moreover, pasireotide decreased Akt phosphorylation and reversed everolimus-induced Akt hyperphosphorylation to a higher degree than octreotide. Using 4E-BP1 siRNA (si4E-BP), we demonstrated that 4E-BP1 protein silencing significantly reversed the response to everolimus, both alone and in combination with SSAs. Moreover, si4E-BP completely reversed the inhibition of cyclin D1 expression level and the increase in p27kip1 induced by SSAs, both alone and in combination with everolimus. Our results strongly support the need for further studies on the combination of pasireotide and everolimus in medical therapy for meningiomas.


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