The Novel SSTR3 Full Agonist ITF2984 Shows Antitumor Properties against Pancreatic Neuroendocrine Tumors

Somatostatin analogs (SSAs) binding to and activating somatostatin receptors (SSTRs) have been extensively used for the treatment of neuroendocrine tumors (NETs). The currently approved synthetic SSAs have high affinity for SSTR2 (octreotide/lanreotide) or for SSTR2 and SSTR5 (pasireotide). These agents have shown symptom control and antiproliferative effects in subsets of NET patients and this was associated with the expression of the targeted SSTRs. Pancreatic NETs (Pan-NETs) are uncommon tumors with a propensity to metastasize. For unresectable advanced Pan-NETs expressing SSTRs, SSAs are the first-line medical therapy. Pan-NETs express mainly SSTR1, SSTR2, and SSTR3 and thus should respond to agonists targeting SSTR3.

We evaluated the efficacy of ITF2984, a novel multireceptor agonist with specificity for SSTR3, against Pan-NET cells representative of well-differentiated, functioning tumors, and expressing high levels of SSTR3. The effect of ITF2984 on cell proliferation/viability and on its ability to promote apoptosis and suppress hormone secretion was evaluated in 2D and 3D organotypic culture systems. Pasireotide was tested in parallel for comparative purposes.

We found that ITF2984 is as effective as pasireotide at inhibiting both proliferation/viability and hormone secretion, as well as at inducing apoptosis of Pan-NET cells grown as both 2D monolayers and 3D spheroids. High-dose ITF2984 elicits structural alterations in Pan-NET 3D spheroids compatible with cell death more effectively than pasireotide. Altogether, ITF2984 may represent a useful alternative to pasireotide for the medical treatment of Pan-NETs and other tumors with elevated SSTR3 expression.