419PD - Strong additive effect of everolimus and octreotide or pasireotide on meningioma cells in vitro: a new therapeutic strategy for these tumors
|Date||29 September 2012|
|Event||ESMO Congress 2012|
|Topics|| Basic Science
Central Nervous System Malignancies
A. Barlier1, T. Graillon2, C. Defilles3, A. Mohamed4, A. Saveanu5, D. Figarella-Branger6, O. Chinot7, P. Roche8, A. Enjalbert4, H. Dufour2
Meningiomas are the most frequent brain tumors after 35 years-old. When total surgical removal is not possible, radiotherapy and radiosurgery are able to control tumoral growth in some cases. But no chemotherapy has ever been demonstrated to be really efficient. Then, in cases of recurrence (particularly in WHO grade 2 and 3 meningiomas), no therapeutic exist at present, leading to fatal issue. Pi3Kinase-Akt-mTor pathway is activated in meningiomas, due to Merlin protein (encoded by NF2 gene) inactivation. SST2 somatostatin receptors are strongly expressed in meningiomas. These receptors are targeted by somatostatin agonists (octreotide and a new “pan-sst” agonist, pasireotide) which antiproliferative effect is known in other types of tumors. The aim of our study is to test in vitro effects of m-Tor inhibitor (Everolimus) and/or somatostatin agonists Octreotide or pasireotide, on human meningiomas in primary culture. By real time PCR, we found that sst2 was expressed in all meningiomas. The expression level of Merlin was highly variable between tumors and was inversely correlated with mTor pathway activation (p < 0.025). Everolimus decreased cell viability in a dose dependent manner, in the 10 analyzed meningiomas, including that of grade 2 and 3. However, an increase in AkT activation was observed. In neuroendocrine cell lines, octreotide is able to decrease AKT activation through a direct interaction between sst2 and the p85, the regulatory subunit of Pi3Kinase. In primary culture of meningiomas, we demonstrated that octreotide and pasireotide were able to decrease cell viability in a dose dependant manner by inducing inhibition of AKT activation. A clear additive effect between everolimus and octreotide or pasireotide was observed on cell viability on the 6 analysed tumors including grades 2 and 3: the percentage of cell viability inhibition, around -25% under one drug, decrease to -40% under mTor inhibitors plus somatostatin analogs. Moreover an additive effect of both drugs was clearly observed on the AKT and mTor pathway This study is the first proof of concept in vitro on the interest of everolimus with octreotide or pasireotide to control tumoral growth of human meningiomas. This study clearly set up the foundations of clinical trials.Disclosure
A. Barlier: the research prgramm was partially supported by Novartis.
All other authors have declared no conflicts of interest.