Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasias that originate from neuroendocrine cells in various organs, including the pancreas and pituitary gland. Pancreatic NETs (PanNETs) and pituitary adenomas/NETs represent clinically relevant subtypes, typically characterized by the expression of somatostatin receptors (SSTRs). These receptors represent key therapeutic targets for both somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT). Currently approved SSAs exhibit high affinity for specific SSTR subtypes, with octreotide and lanreotide targeting SSTR2, while pasireotide binds to SSTR5, SSTR3 and SSTR2. Despite the availability of these SSAs, these peptides may not be suitable for all patients due to variable SSTR expression, limited efficacy in aggressive or advanced tumors, and the potential development of resistance. As a result, developing novel compounds targeting NET-specific pathways is crucial to improving patient outcomes. In this study, we tested 5 newly synthesized SSAs having high affinity for SSTR2 and SSTR5 that are being developed as SSAs and PRRT.

As experimental models, we selected the NT-3 and AtT-20 cell lines, derived from a human well-differentiated pancreatic NET (Pan-NET) and a murine pituitary adenoma cell line, respectively. NT-3 cells were chosen based on their low proliferation rate, sustained SSTR expression, and insulin-secreting capability, making them a representative in vitro model for Pan-NETs. Similarly, AtT-20 cells, which secrete ACTH, serve as a well-established model for pituitary adenomas/NETs. Since SSAs are expected to inhibit tumor growth and suppress hormone secretion, we assessed the short-term effects of the five peptides on these features using proliferation/viability assays (WST-1, cell count) and hormone secretion measurements (ELISA for insulin or ACTH) in 2D cultures.

In the pancreatic NT-3 cell model, all tested peptides strongly inhibited insulin secretion at doses ranging from 5 to 100 nM, and significantly blunted proliferation compared to untreated controls. In the pituitary AtT-20 cell model, two out of five peptides had clear inhibitory effects on ACTH secretion, while the peptides also appeared to limit tumor cell growth.

These results indicate that the newly synthesized SSAs effectively inhibit both hormone secretion and cell proliferation in NET models. Further investigations in 3D cultures and in vivo models will be essential to confirm their therapeutic potential and optimize their clinical applicability.