ECE2024 Rapid Communications Rapid Communications 9: Pituitary and Neuroendocrinology | Part II (7 abstracts)
The novel SST3 agonist ITF2984 exerts antimitotic and proapoptotic effects in human non-functioning pituitary neuroendocrine tumor (NF-PitNET) cells
Genesio Di Muro 1,2 , Rosa Catalano 2 , Donatella Treppiedi 3 , Anna Maria Barbieri 2 , Federica Mangili 3 , Giusy Marra 2 , Sonia Di Bari 2 , Emanuela Esposito 2,4 , Emma Nozza 2,4 , Andrea Lania 5,6 , Marco Locatelli 7,8 , Daniela Modena 9 , Christian Steinkuhler 9 , Erika Peverelli 2,3 & Giovanna Mantovani 2,3
1University Sapienza of Rome, Dipartimento di Medicina Sperimentale, Rome, Italy; 2Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 3Endocrinology unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 4PhD Program in Experimental Medicine, University of Milan, Milan, Italy; 5Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; 6Endocrinology and Diabetology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Hu-manitas Research Hospital, Rozzano, Italy; 7Neurosurgery Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 8Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; 9Preclinical R&D, Italfarmaco Group, Cinisello Balsamo, Italy
Non-functioning pituitary neuroendocrine tumors (NF-PitNETs) are still orphan of medical therapy. The drmgs approved for the other types of PitNETs, e.g. somatostatin analogues (SSA) with high affinity for somatostatin receptors (SSTs) type 2 (SST2) and 5 (SST5) are poorly efficacious in NF-PitNETs. Among SSTs, NF-PitNETs express high levels of SST3, a receptor that can mediate antiproliferative and apoptotic signaling. ITF2984 is a pan-SST ligand with high affinity for SST3, able to induce SST3 internalization and phosphorylation, to trigger G-protein signaling in vitro and to exert antitumoral activity in MENX rat model. Aim of the present study was to test the antiproliferative and proapoptotic effects of ITF2984 in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTs expression profile. We treated primary cells derived from 23 NF-PitNETs with ITF2984, octreotide (SSA with high affinity for SST2), pasireotide (SSA with high affinity for SST5) or cabergoline (DRD2 agonist) and we measured cell proliferation (by BrdU incorporation assay) and apoptosis (by caspase 3/7 activity assay). The expression of SST3, SST2 and SST5 in tumor tissues was analysed by qRT-PCR and western blot. Our results demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08) %, P<0.001 vs basal, n=19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, P<0.001 vs basal, n=17 NF-PitNETs). On the contrary, in the same tumors no effect was observed after octreotide, pasireotide, or cabergoline treatment. Receptor expression analysis revealed that SST3, SST2 and SST5 transcripts were expressed at similar levels in tumor tissues, and a positive correlation was found between SST3 and SST5 protein levels. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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