Cell specific interaction of pasireotide: review of preclinical studies in somatotroph and corticotroph pituitary cells

Abstract

Background: Pasireotide is a second-generation somatostatin (SRIF) receptor ligand (SRL), approved for medical treatment of acromegaly and Cushing's disease (CD). The molecule is a stable cyclohexapeptide synthetized based on SRIF structure. Differently from first-generation SRLs (e.g. octreotide), preferentially binding somatostatin receptor (SST) subtype 2 (SST₂), pasireotide has high affinity for multiple SSTs (SST₅ > SST₂ > SST₃ > SST₁). Interestingly, early preclinical studies demonstrated that pasireotide shows distinct functional properties compared to SRIF and first-generation SRLs when binding SSTs.

Methods: We aimed to highlight the differential receptor-targeted action of pasireotide in the treatment of somatotroph and corticotroph adenomas, throughout the critical revision of preclinical studies carried out on acromegaly and CD models.

Results: Different authors demonstrated that the antisecretory effect of pasireotide in somatotroph adenoma cell cultures is comparable to that of the SST₂-preferential agonist octreotide. Some reports even show a direct correlation between SST₂ mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST₂ in driving pasireotide efficacy in somatotropinomas in vitro. On the other hand, the inhibitory effect of pasireotide on ACTH secretion in corticotropinoma cells seems to be mainly mediated by SST₅. Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST₂ preferential agonists, while functional studies confirm the pivotal role of SST₅ targeting in corticotroph cells.

Conclusions: The analysis of preclinical studies carried out in somatotroph and corticoph adenomas points out that pasireotide shows a cell-specific activity, exerting its biological effects via different SSTs in the different adenoma histotypes.

Keywords: ACTH-secreting; GH-secreting; Pasireotide; Pituitary adenomas; Primary cultures.