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Identification of a Novel SSTR3 full agonist for the treatment of nonfunctioning pituitary adenomas.
Cancers 15:19 (2023)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Itf2984 ; Nonfunctioning Pituitary Adenomas (nfpas) ; Somatostatin Agonists (ssas) ; Somatostatin Receptor 3 (sstr3); Somatostatin Receptors; Expression; Binding; Phosphorylation; Pasireotide; Release; Analogs; Som230; Cilia
ISSN (print) / ISBN
2072-6694
Zeitschrift
Cancers
Quellenangaben
Band: 15,
Heft: 13,
Artikelnummer: 19
Verlag
MDPI
Verlagsort
St Alban-anlage 66, Ch-4052 Basel, Switzerland
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Diabetes and Cancer (IDC)