Objective: 

Pasireotide (SOM230) is a novel multi-receptor ligand somatostatin analogue with high affinity for somatostatin receptor subtypes sst1,2,3 and sst5. This abstract looks at the mechanism of action of pasireotide in order to determine the underlying basis for the clinical efficacy of pasireotide.

Methods: 

Preclinical and clinical studies have demonstrated antisecretory and antiproliferative effects of pasireotide in pituitary adenomas and GEP-NETs. Data from these studies have been evaluated to elucidate the possible mechanism of action of pasireotide in these settings.

Results: 

Pasireotide is a stable cyclohexapeptide and binds to sst1,2,3 and sst5, with IC50 values of 9.3, 1.0, 1.5 and 0.16 nmol/L. Compared with octreotide, which is currently the gold-standard used in the clinic for the treatment of acromegaly and GEP-NET tumors, pasireotide has a 30-, 5- and 40-fold higher affinity for sst1,3 and sst5, and a slightly lower affinity for sst2. GH- and ACTH-secreting pituitary adenomas express primarily sst2 and sst5. The antisecretory effect of somatostatin analogues on GH is mediated by sst2 and sst5, whereas hepatic GH-induced IGF-I production is inhibited via sst2 and/or sst3-mediated decreases in IGF-I gene transcription. In corticotroph adenomas, cortisol-induced downregulation of sst2 may explain the lack of efficacy of octreotide and lanreotide in Cushing's disease. Pasireotide inhibits ACTH via sst5 receptors in rats, which are rapidly recycled/recruited from intracellular stores after agonist activation, thereby lowering cortisol levels and restoring sst2 expression, suggesting enhanced ACTH inhibition by a sst2/sst5 ligand. GEP-NETs express multiple sst subtypes, mainly sst1,2 and sst5, and the antisecretory and antiproliferative effects of somatostatin analogues in GEP-NETs are mediated by sst1,2,3 and sst5. In HEK293 cells, octreotide but not pasireotide induces internalization of sst2 after drug exposure, possibly explaining the tachyphylaxis seen with octreotide in GEP-NETs, and suggesting persistent efficacy for pasireotide.

Conclusion: 

By acting at multiple sst receptors, pasireotide has the potential to be an effective new treatment for patients with de novo, persistent or refractory acromegaly and GEP-NETs. Most significantly, this compound offers the first medical treatment option for patients with primary Cushing's disease. Due to its multireceptor binding profile, which resembles natural human somatostatin, this compound may also represent an effective treatment option in other pathohysiological conditions, characterized by excess secretion of hormones.