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

Purpose: 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 SST and SST. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST-agonists and characterize their effects on experimental NFPT models.

Experimental Design: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST-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 SST-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST-agonist.

Results: We successfully identified the first SST-agonist peptides. SST-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis , and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST-agonist treatments. Concurrently, silencing increased cell viability in a subset of NFPTs.

Conclusions: This study demonstrates that SST-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.