2. Academic Validation
  3. Identification of a Novel SSTR3 Full Agonist for the Treatment of Nonfunctioning Pituitary Adenomas

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

  • Cancers (Basel). 2023 Jun 30;15(13):3453. doi: 10.3390/cancers15133453.
Daniela Modena 1,  Maria Luisa Moras 1,  Giovanni Sandrone 1,  Andrea Stevenazzi 1,  Barbara Vergani 1,  Pooja Dasgupta 2,  Andrea Kliever 2,  Sebastian Gulde 3 4,  Alessandro Marangelo 3 4 5,  Mathias Schillmaier 6 7,  Raul M Luque 8 9 10 11,  Stephen Bäuerle 12,  Natalia S Pellegata 3 4 5,  Stefan Schulz 2,  Christian Steinkühler 1
Affiliations

Affiliations

  • 1 Preclinical R&D, Italfarmaco Group, 20092 Cinisello Balsamo, Milan, Italy.
  • 2 Institute of Pharmacology and Toxicology, Universitätsklinikum Jena, Friedrich-Schiller-Universität, 07747 Jena, Germany.
  • 3 Institute for Diabetes and Cancer, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 4 Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 5 Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy.
  • 6 Department of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 80333 Munich, Germany.
  • 7 Department of Diagnostic and Interventional Radiology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 80333 Munich, Germany.
  • 8 Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain.
  • 9 Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.
  • 10 Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain.
  • 11 CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain.
  • 12 Department of Mathematics, Technical University Munich, 85748 Garching, Germany.
PMID: 37444563 DOI: 10.3390/cancers15133453
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.

Keywords

ITF2984; nonfunctioning pituitary adenomas (NFPAs); somatostatin agonists (SSAs); somatostatin receptor 3 (SSTR3).

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