A Somatostatin Receptor Subtype-3 (SST 3 ) 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 ₂ and SST ₅ . Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST ₂ . However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST ₃ and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST ₃ -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 ₃ -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 ₃ -agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST ₃ -agonist.
Results: We successfully identified the first SST ₃ -agonist peptides. SST ₃ -agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro , and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST ₃ -agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST ₃ than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST ₃ -agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs.
Conclusions: This study demonstrates that SST ₃ -agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST ₃ , suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
(©2019 American Association for Cancer Research.)