Clinically non-functioning pituitary neuroendocrine tumors (NF-PitNETs) lack effective medical therapies, and the role of somatostatin receptor ligands (SRLs) and dopamine agonists (DAs) in this setting is controversial. We evaluated the in vitro response of NF-PitNETs to multiple SRL and/or DA treatments, focusing on the role of receptor expression and tumor characteristics in driving tumor response. Forty-four NF-PitNET primary cultures were treated (72 h, 10 nM) with octreotide (OCT), pasireotide (PAS), OCT + PAS, BIM-53097 (D2R agonist), BIM-53097 + PAS, and BIM-23B065 (SSTR2/SSTR5/D2R preferential ligand) to evaluate cell proliferation inhibition. Tumors were considered responders to a treatment when a >= 20% reduction in cell proliferation was observed (vs. control); responder tumors to at least one tested condition were classified into the "responder group" for further analysis. Somatostatin (SSTRs) and dopamine type 2 receptor (D2R) expression were evaluated through immunohistochemistry. Data on radiological invasiveness, proliferation indices (Ki67%, mitoses), and p53 immunostaining were collected. Tumor grade was determined using Trouillas and PANOMEN-3 classifications. Median patient age at surgery was 60.3 years (IQR 49.7-70.7), 29 were males (71%). Overall, no significant in vitro inhibition of cell proliferation was observed [ranging from -4.2% (OCT and PAS) to -7.4% (BIM-53097 + PAS)]. However, 13 cultures (30%) were included in the "responder group" [mean inhibition ranging from -18.6% (OCT) to -27.7% (BIM-53097 + PAS)]. D2R was the most expressed receptor (median IRS 8, IQR 6-8), followed by SSTR1 and SSTR2 (median IRS 4, IQR 3-6); SSTR3 and SSTR5 expression was low. In the whole cohort, OCT and PAS efficacy directly correlated with SSTR2 (p = .013 and p = .027, respectively). D2R and SSTR2 expression was higher in responders vs. non-responders to BIM-23B065 (p = .017 and p = .042, respectively). ROC curve analysis discriminates BIM-23B065 responders based on D2R and SSTR2 expression with acceptable ability (AUC = 0.784 and AUC = 0.743, respectively). However, the "responder group" did not differ significantly from the "non-responder group" with respect to patient demographics, tumor clinical-pathological characteristics, receptor expression, and grading. In conclusion, we confirm the limited efficacy of SRL and DA treatment in NF-PitNETs. D2R and SSTR2 can discriminate tumors responsive to BIM-23B065. As concerns the other tested compounds, none of the tumor parameters evaluated demonstrated robust predictive value for NF-PitNET in vitro response.
Predictors of in vitro response to somatostatin and dopamine receptor‐targeted treatments are lacking in clinically non‐functioning pituitary tumors
Claudia Campana;Anna Arecco;Paolo Nozza;Mara Boschetti;Gianluigi Zona;Diego Ferone;Marica Arvigo;Federico Gatto
2026-01-01
Abstract
Clinically non-functioning pituitary neuroendocrine tumors (NF-PitNETs) lack effective medical therapies, and the role of somatostatin receptor ligands (SRLs) and dopamine agonists (DAs) in this setting is controversial. We evaluated the in vitro response of NF-PitNETs to multiple SRL and/or DA treatments, focusing on the role of receptor expression and tumor characteristics in driving tumor response. Forty-four NF-PitNET primary cultures were treated (72 h, 10 nM) with octreotide (OCT), pasireotide (PAS), OCT + PAS, BIM-53097 (D2R agonist), BIM-53097 + PAS, and BIM-23B065 (SSTR2/SSTR5/D2R preferential ligand) to evaluate cell proliferation inhibition. Tumors were considered responders to a treatment when a >= 20% reduction in cell proliferation was observed (vs. control); responder tumors to at least one tested condition were classified into the "responder group" for further analysis. Somatostatin (SSTRs) and dopamine type 2 receptor (D2R) expression were evaluated through immunohistochemistry. Data on radiological invasiveness, proliferation indices (Ki67%, mitoses), and p53 immunostaining were collected. Tumor grade was determined using Trouillas and PANOMEN-3 classifications. Median patient age at surgery was 60.3 years (IQR 49.7-70.7), 29 were males (71%). Overall, no significant in vitro inhibition of cell proliferation was observed [ranging from -4.2% (OCT and PAS) to -7.4% (BIM-53097 + PAS)]. However, 13 cultures (30%) were included in the "responder group" [mean inhibition ranging from -18.6% (OCT) to -27.7% (BIM-53097 + PAS)]. D2R was the most expressed receptor (median IRS 8, IQR 6-8), followed by SSTR1 and SSTR2 (median IRS 4, IQR 3-6); SSTR3 and SSTR5 expression was low. In the whole cohort, OCT and PAS efficacy directly correlated with SSTR2 (p = .013 and p = .027, respectively). D2R and SSTR2 expression was higher in responders vs. non-responders to BIM-23B065 (p = .017 and p = .042, respectively). ROC curve analysis discriminates BIM-23B065 responders based on D2R and SSTR2 expression with acceptable ability (AUC = 0.784 and AUC = 0.743, respectively). However, the "responder group" did not differ significantly from the "non-responder group" with respect to patient demographics, tumor clinical-pathological characteristics, receptor expression, and grading. In conclusion, we confirm the limited efficacy of SRL and DA treatment in NF-PitNETs. D2R and SSTR2 can discriminate tumors responsive to BIM-23B065. As concerns the other tested compounds, none of the tumor parameters evaluated demonstrated robust predictive value for NF-PitNET in vitro response.
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