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

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.

Clinical Significance of Somatostatin Receptor (SSTR) 2 in Meningioma

“…Somatostatin analogs have already achieved promising effects in the treatment of high-SSTR2-expression tumors, such as gastroenteropancreatic neuroendocrine tumors and GH-secreting pituitary adenomas (78,79). The therapeutic efficacy of somatostatin analogs for meningiomas in vitro has been confirmed in various studies (27,77,80,81). For example, Graillon et al demonstrated that octreotide significantly decreased proliferation in 88% of fresh primary meningioma cells (82).…”

“…The direct and indirect antitumor mechanisms ( Figure 2 ) of the SSTR2 ligands–somatostatin analogs for the treatment of meningioma have been explored in several preclinical researches. Somatostatin or its analogs bind to SSTR2, leading to the activation of specific tyrosine phosphatases (SHP1 and SHP2) and the inhibition of the PI3K/Akt pathways, which mediate its direct antitumor effects through the induction of cyclin-dependent kinase inhibitors and cell cycle arrest ( 27 , 80 , 81 , 83 – 87 ). The indirect antitumor mechanisms of somatostatin analogs incorporate (1) reduction of angiogenesis, particularly by inhibiting vascular endothelial growth factor (VEGF) secretion; (2) suppression of growth factors and hormone secretion that will drive tumor growth; and (3) stimulation of natural antitumor mechanisms ( 27 , 84 , 86 – 88 ).…”

An Overview of Meningiomas

“…No results are yet available for these studies. Application of agents targeting the mTOR-pathway, which has been successful in human meningioma cell lines in vitro [84,85], is currently being examined in trials with everolimus (NCT01880749 and NCT01419639) and vistusertib (AZD2014, NCT03071874 and NCT02831257). Everolimus is also being studied in combination with the somatostatin receptor analog octreotide (CAVOREM, NCT02333565) in recurrent meningioma.…”

Systemic therapy for relapsed/refractory meningioma: Is there potential for antiangiogenic agents?

“…36 In vitro studies suggested that pasireotide, a longacting somatostatin analog, may be more effective than octreotide at inhibiting tumor growth. 37 Furthermore, Norden et al 38 evaluated pasireotide in a phase II trial of 34 patients with recurrent or progressive meningioma. In this cohort, the PFS-6 was 17% for patients with WHO grade II or III disease and 50% for grade I disease.…”