A somatostatin receptor subtype-3 (SST3) peptide agonist shows antitumor effects in experimental models of Nonfunctioning Pituitary Tumors

A somatostatin receptor subtype-3 (SST3) peptide agonist shows antitumor effects in experimental models of Nonfunctioning Pituitary Tumors:

Purpose: Somatostatin-analogs (SSAs) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNETs). 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, non-functioning 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. Experimental Design: 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. Results: We successfully identified the first SST₃-agonist peptides. SST₃-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 SST₃-agonists defined two NFPTs 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, SSTR3-silencing increased cell-viability in a subset of NFPTs. Conclusions: 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.