Predictors of in vitro response to somatostatin and dopamine receptor-targeted treatments are lacking in clinically non-functioning pituitary tumors.
The study confirms limited efficacy of somatostatin receptor ligands and dopamine agonists in non-functioning pituitary tumors, with only a small percentage showing any response.
Where it sits
this study against the rest of the pasireotide corpusSummary and findings
This study evaluated the in vitro response of clinically non-functioning pituitary neuroendocrine tumors (NF-PitNETs) to various somatostatin receptor ligands and dopamine agonists. A total of 44 NF-PitNET primary cultures were treated with multiple compounds for 72 hours at a concentration of 10 nM. The study found limited efficacy of these treatments in inhibiting cell proliferation.
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.
Background
This paper addresses the lack of effective medical therapies for clinically non-functioning pituitary neuroendocrine tumors (NF-PitNETs) and evaluates the role of somatostatin receptor ligands (SRLs) and dopamine agonists (DAs). Prior studies have shown mixed results regarding the efficacy of these treatments in this context. Understanding the in vitro response of NF-PitNETs to these agents could provide insights into potential therapeutic strategies.
Methods
The study utilized an in vitro design with 44 primary cultures of NF-PitNETs treated for 72 hours with various agents including pasireotide (10 nM). The primary outcome measure was cell proliferation inhibition, defined as a ≥20% reduction compared to control. Secondary measures included receptor expression and tumor characteristics assessed through immunohistochemistry.
Results
Overall, no significant in vitro inhibition of cell proliferation was observed, with results ranging from -4.2% to -7.4%. However, 30% of cultures were classified as responders, with mean inhibition from -18.6% to -27.7%. D2R expression was found to be the most prevalent among receptors, and efficacy of OCT and PAS correlated with SSTR2 expression (p=0.013 and p=0.027).
Interpretation
The findings suggest limited clinical relevance of SRLs and DAs in treating NF-PitNETs, as the observed effect sizes are small and do not indicate a robust response. While D2R and SSTR2 expression may help identify responders to BIM-23B065, the overall lack of significant predictive factors limits the applicability of these findings in clinical practice. This study aligns with previous literature indicating challenges in treating NF-PitNETs effectively.
Key findings
- No significant in vitro inhibition of cell proliferation observed, ranging from -4.2% (OCT and PAS) to -7.4% (BIM-53097 + PAS).
- 13 cultures (30%) were classified as responders with mean inhibition ranging from -18.6% (OCT) to -27.7% (BIM-53097 + PAS).
- D2R expression was the highest with a median IRS of 8 (IQR 6-8).
- OCT and PAS efficacy correlated with SSTR2 expression (p=0.013 and p=0.027, respectively).
- ROC curve analysis showed AUC of 0.784 and AUC of 0.743 for D2R and SSTR2 expression in discriminating BIM-23B065 responders.
Limitations
- small n=44 for in vitro analysis
- no significant in vitro inhibition observed
- limited predictive value of tumor parameters
- short treatment duration of 72 hours
- single-site study