The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary
Genesio Di Muro1,2, Rosa Catalano1, Donatella Treppiedi3
1Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
Abstract:
Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We 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) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.
Insights
ITF2984, a novel somatostatin receptor ligand, effectively reduced tumor cell proliferation and increased apoptosis in human pituitary tumors (NF-PitNETs). This pan-SSTR ligand shows promise for treating these rare neuroendocrine tumors.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Pituitary tumors, specifically Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNETs), often express high levels of somatostatin receptor 3 (SSTR3).
- Existing somatostatin receptor ligands (SRLs) targeting SSTR2 and SSTR5 show limited efficacy in NF-PitNETs due to their SSTR3 expression profile.
Purpose of the Study:
- To evaluate the antiproliferative and proapoptotic effects of ITF2984, a pan-SSTR ligand with high affinity for SSTR3, in primary cultured NF-PitNET cells.
- To characterize the somatostatin receptor (SSTR) expression profile in these human tumor samples.
Main Methods:
- Primary NF-PitNET cells from 23 human tumors were treated with ITF2984.
- Comparative treatment with octreotide, pasireotide, or cabergoline was performed on a subset of samples.
- Cell proliferation and apoptosis were measured.
- SSTR3, SSTR2, and SSTR5 expression was analyzed using qRT-PCR and Western blot.
Main Results:
- ITF2984 significantly reduced cell proliferation by 40.8% (p < 0.001) and increased apoptosis by 41.4% (p < 0.001) in all tested NF-PitNETs.
- In contrast, octreotide, pasireotide, and cabergoline showed efficacy only in a subset of tumors.
- SSTR3 expression levels did not correlate with the antiproliferative or proapoptotic response to ITF2984.
Conclusions:
- ITF2984 demonstrates consistent antiproliferative and proapoptotic activity across diverse NF-PitNETs, irrespective of SSTR3 expression levels.
- These findings support the potential therapeutic application of ITF2984 for NF-PitNETs.
- ITF2984 represents a promising novel therapeutic agent for pituitary neuroendocrine tumors.
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