Anti-Secretory and Anti-Proliferative Actions of Next-Generation Dual Subtype 2 and 5 Somatostatin Receptor Ligands in Neuroendocrine Tumor Models

Francesco Fedeli¹Margarita Bistika¹Francesco Ascione¹Alessandro Marangelo²Fabio Luca Guzzi¹Jörg Schrader^3,4ALAN HARRIS⁵Natalia Simona Pellegata^1*

• ¹Universita di Pavia, Pavia, Italy
• ²Helmholtz Zentrum Munchen Helmholtz Diabetes Center, Neuherberg, Germany
• ³Ruhr-Universitat Bochum, Bochum, Germany
• ⁴Klinikum Nordfriesland, Husum, Germany
• ⁵New York University Grossman School of Medicine, New York, United States

Introduction: First-generation somatostatin receptor ligands (SRLs) mainly target SSTR2, whereas neuroendocrine tumors (NETs) often express multiple SSTR subtypes, frequently SSTR5. Dual SSTR2/SSTR5 targeting may enhance anti-hormonal and antiproliferative effects. We evaluated five novel dual SSTR2/SSTR5 agonists (SMTR-001 to SMTR-005) in preclinical NET models to assess their anti-secretory and anti-proliferative effects in representative preclinical NET models. Methods: The human insulinoma-derived NT-3 cell line and the murine AtT-20 corticotroph cell line, both expressing SSTR2 and SSTR5, were treated with 1–50 nM of the novel SRLs or reference agents (octreotide, pasireotide). Insulin and ACTH secretion were quantified by ELISA and cell viability was measured after 72 h (AtT-20) or 5 days (NT-3). A putative lead compound, SMTR-002, was further tested in 3D spheroid cultures of NT-3 cells. Intracellular cAMP modulation was evaluated after forskolin stimulation in AtT-20 cells. Results: In NT-3 cells, all dual SRLs inhibited insulin secretion (−65% to −95%), with SMTR-002, SMTR-004, and SMTR-005 showing significantly greater inhibition than octreotide at 10 nM. Each compound also reduced cell proliferation (−30% to −44%). In 3D cultures of NT-3 cells, SMTR-002 reduced insulin secretion to a degree comparable to octreotide but, unlike octreotide, significantly decreased cell proliferation. In AtT-20 cells, four novel SRLs significantly reduced ACTH secretion (-11% to -69%), with SMTR-001 and SMTR-004 showing efficacy comparable to pasireotide. SMTR-002 and SMTR-003 demonstrated the greatest antiproliferative effects (−53% and −48% at 10 nM). In AtT-20 cells, SMTR-002 also suppressed forskolin-induced cAMP accumulation more strongly than reference SRLs. Conclusion: Dual SSTR2/SSTR5 agonists exhibit antisecretory and antiproliferative activity in NET models that was similar or even superior to reference SRLs. These findings support their further development as next-generation SRLs for SSTR2/5-expressing tumors.