Identification of a Novel SSTR3 Full Agonist for the Treatment of Nonfunctioning Pituitary Adenomas

Abstract

Somatostatin receptor (SSTR) agonists have been extensively used for treating neuroendocrine tumors. Synthetic therapeutic agonists showing selectivity for SSTR2 (Octreotide) or for SSTR2 and SSTR5 (Pasireotide) have been approved for the treatment of patients with acromegaly and Cushing’s syndrome, as their pituitary tumors highly express SSTR2 or SSTR2/SSTR5, respectively. Nonfunctioning pituitary adenomas (NFPAs), which express high levels of SSTR3 and show only modest response to currently available SSTR agonists, are often invasive and cannot be completely resected, and therefore easily recur. The aim of the present study was the evaluation of ITF2984, a somatostatin analog and full SSTR3 agonist, as a new potential treatment for NFPAs. ITF2984 shows a 10-fold improved affinity for SSTR3 compared to Octreotide or Pasireotide. Molecular modeling and NMR studies indicated that the higher affinity for SSTR3 correlates with a higher stability of a distorted β-I turn in the cyclic peptide backbone. ITF2984 induces receptor internalization and phosphorylation, and triggers G-protein signaling at pharmacologically relevant concentrations. Furthermore, ITF2984 displays antitumor activity that is dependent on SSTR3 expression levels in the MENX (homozygous mutant) NFPA rat model, which closely recapitulates human disease. Therefore, ITF2984 may represent a novel therapeutic option for patients affected by NFPA.

The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells

“…These Sprague Dawley rats bear germline frameshift mutations in the p27 gene and are characterized by the spontaneous development of a multiple endocrine syndrome within their first year of life with 100% penetrance, with pituitary tumors that share features with human gonadotroph tumors [23,24]. ITF2984 demonstrated significant antitumor activity in the female rats, who showed higher expression levels of SSTR3 compared to the males [22].…”

“…Interestingly, a novel SSTR3 agonist, ITF2984, has been recently characterized [22]. Although this molecule was originally developed as a pan-SSTR agonist, it shows a 10fold improved affinity for SSTR3 compared to octreotide or pasireotide; it acts as a full agonist of SSTR3 in in vitro assays, promoting SSTR3 internalization and phosphorylation, and inducing G-protein signaling [22].…”

“…Interestingly, a novel SSTR3 agonist, ITF2984, has been recently characterized [22]. Although this molecule was originally developed as a pan-SSTR agonist, it shows a 10fold improved affinity for SSTR3 compared to octreotide or pasireotide; it acts as a full agonist of SSTR3 in in vitro assays, promoting SSTR3 internalization and phosphorylation, and inducing G-protein signaling [22]. Moreover, ITF2984 has been tested in vivo in the MENX rat model, characterized by the spontaneous development of pituitary tumors that share features with human gonadotroph tumors [23,24].…”

“…Moreover, ITF2984 has been tested in vivo in the MENX rat model, characterized by the spontaneous development of pituitary tumors that share features with human gonadotroph tumors [23,24]. ITF2984 demonstrated significant antitumor activity in female MENX rats, who showed higher expression levels of SSTR3 compared to males [22]. However, the effects of ITF2984 on cell growth have never been tested in primary cultured human NF-PitNET cells, nor in other cell lines.…”

Somatostatin and Somatostatin Receptors in Tumour Biology

“…Although all SSTR subtypes are expressed in NFPA and efficacy is linked to the expression of receptor subtypes, the question of debate is whether it is SSTR1 or SSTR3 that is highly efficacious. Recently, using a NFPA rat model, SSTR3’s new full agonist, namely ITF2984, was shown to exhibit antitumor activity [ 340 ]. Like SSTR subtypes, the efficacy of D2R was also determined with the expression level of D2R.…”