A Somatostatin Receptor Subtype-3 (SST₃) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors.

Abstract

Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST₂ and SST₅. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST₂. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST₃ and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST₃-agonists and characterize their effects on experimental NFPT models. Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST₃-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST₃-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST₃-agonist. We successfully identified the first SST₃-agonist peptides. SST₃-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis <i>in vitro</i>, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST₃-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST₃ than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST₃-agonist treatments. Concurrently, <i>SSTR3</i> silencing increased cell viability in a subset of NFPTs. This study demonstrates that SST₃-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST₃, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.