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 (SST 2 ), pasireotide has high affinity for multiple SSTs (SST 5 > SST 2 > SST 3 > SST 1 ). 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 SST 2 -preferential agonist octreotide. Some reports even show a direct correlation between SST 2 mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST 2 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 SST 5 . Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST 2 preferential agonists, while functional studies confirm the pivotal role of SST 5 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.

Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms

“…demonstrated that, in HEK 293 cells stably transfected with human SST 5 , PAS was superior to OCT in decreasing intracellular cAMP levels and in the stimulation of ERK1/2 phosphorylation [104]. This evidence, derived from transfected cell models, is in line with subsequent preclinical studies carried out in corticotroph pituitary cells (mainly expressing SST 5 among all SST subtypes), which show a greater efficacy of PAS, compared to first-generation SRLs, in the inhibition of basal and/or CRH-stimulated ACTH secretion [105,106].…”

AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients

“…Patient 1 was never treated with radiotherapy, so the most likely explanation currently is that chronic pasireotide LAR was responsible. The mechanism by which this involution occurred is unknown but we suggest that activation of SST5-predominant anti-proliferative and pro-apoptotic pathways as seen in corticotropes could also be involved in somatotropinomas with disordered AIP function (24, 25). Patient 2 has had a shorter duration of pasireotide LAR treatment overall, but as seen in Fig.…”

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

“…In functioning corticotroph tumors, pasireotide is indicated in order to decrease hypercortisolism. In vitro studies on corticotroph tumor cells have found a decrease in ACTH release following use of pasireotide, which seems to be mediated by SST5 (12,17,40,41,42). Indeed, SST5 is the most highly expressed somatostatin receptor in corticotroph tumors (12,20,42), and it has been shown in previous studies that octreotide, which targets SST2, is less effective than pasireotide in decreasing cortisol levels and that SST2 is downregulated in the context of exposure to high glucocorticoid levels (41, 42).…”

“…In vitro studies on corticotroph tumor cells have found a decrease in ACTH release following use of pasireotide, which seems to be mediated by SST5 (12,17,40,41,42). Indeed, SST5 is the most highly expressed somatostatin receptor in corticotroph tumors (12,20,42), and it has been shown in previous studies that octreotide, which targets SST2, is less effective than pasireotide in decreasing cortisol levels and that SST2 is downregulated in the context of exposure to high glucocorticoid levels (41, 42). The response rate to pasireotide treatment in Cushing's disease obtained in previously published clinical trials was between 20 to 40% (13,14), which is in agreement with the number of patients with functioning corticotroph tumors expressing SST5 with an IRS score of moderate or strong in our cohort, suggesting that only one-third of functioning corticotroph pituitary tumors are likely to be sensitive to pasireotide treatment.…”