Ex Vivo drug sensitivity in patient-derived 3D cultures in acromegaly and its association with clinical predictors.
The study suggests that ex vivo drug sensitivity testing in patient-derived cultures may help predict responses to treatments like pasireotide in acromegaly, but findings are based on a small sample.
Where it sits
this study against the rest of the pasireotide corpusSummary and findings
This study evaluated the ex vivo drug sensitivity of patient-derived 3D cultures from 27 patients with acromegaly, focusing on pasireotide among other agents. Median cell viability was reduced by 84-86% with responder rates of 33-40%. The findings suggest a correlation between drug response and established clinical predictors.
Abstract
<h4>Purpose</h4>Personalized therapy in acromegaly is limited by interindividual variability in drug responses and the lack of robust markers predicting tumor shrinkage, rather than biochemical control alone. To test whether ex vivo drug-induced viability changes in patient-derived 3D cultures (Pd3D) of GH-secreting pituitary adenomas reflect tumor cell-intrinsic pharmacological sensitivity and align with established clinical predictors.<h4>Methods</h4>Spheroid-based Pd3D cultures were established from 27 patients with acromegaly. Cultures were exposed to octreotide, cabergoline, pasireotide, or vehicle control. We assessed cell viability changes; sample-level responder status (viability reduction vs vehicle, p < 0.05); and associations between responder status and known predictive markers, including clinical characteristics, MRI findings, dynamic drug tests, and pathological features. In 6 cases, AI-based digital image analysis quantified pre- and post-treatment SSTR2 expression in liquid-based cytology (LBC).<h4>Results</h4>All agents modestly reduced median cell viability (84-86%, p < 0.05), with responder rates of 33-40%. Concordance with established predictors was observed: octreotide responders correlated with T2 hypointensity (88% vs 44%, p = 0.04); cabergoline with positive bromocriptine tests (100% vs 45%, p = 0.03); and pasireotide with sparsely granulated patterns (64% vs 19%, p = 0.04). AI-based dynamic analysis demonstrated that ex vivo responders showed relatively stable SSTR2 expression after treatment, whereas nonresponders exhibited marked depletion.<h4>Conclusion</h4>Spheroid-based Pd3D ex vivo viability assays revealed modest but significant cohort-level effects and sample-level concordance with clinical predictors, suggesting its potential utility as an exploratory model. Additionally, AI-based quantification of SSTR2 dynamics captured functional receptor shifts.
Background
This paper addresses the variability in drug responses among patients with acromegaly and the challenge of predicting tumor shrinkage. Previous research has indicated that personalized therapy is hindered by a lack of robust markers. This study is significant as it explores the potential of patient-derived 3D cultures to reflect pharmacological sensitivity and align with clinical predictors.
Methods
Spheroid-based patient-derived 3D cultures were established from 27 patients with acromegaly. The cultures were exposed to pasireotide, octreotide, cabergoline, or vehicle control. The primary outcome measures included cell viability changes and sample-level responder status, assessed for statistical significance at p<0.05.
Results
All agents modestly reduced median cell viability to 84-86%, p<0.05, with responder rates between 33% and 40%. Specific correlations were observed: octreotide responders showed T2 hypointensity at 88% vs 44%, p=0.04; cabergoline responders had positive bromocriptine tests at 100% vs 45%, p=0.03; and pasireotide responders exhibited sparsely granulated patterns at 64% vs 19%, p=0.04.
Interpretation
The findings suggest that while the drug responses are statistically significant, the clinical relevance may be limited due to modest effect sizes. The study's small sample size and reliance on ex vivo models may confound the applicability of the results to broader clinical practice. These results indicate a potential for further exploration of 3D cultures in understanding drug sensitivity in acromegaly.
Key findings
- Median cell viability reduction of 84-86%, p<0.05.
- Responder rates of 33-40% for drug exposure.
- Octreotide responders correlated with T2 hypointensity (88% vs 44%, p=0.04).
- Cabergoline responders correlated with positive bromocriptine tests (100% vs 45%, p=0.03).
- Pasireotide responders correlated with sparsely granulated patterns (64% vs 19%, p=0.04).
Limitations
- small sample size n=27
- ex vivo model may not reflect in vivo responses
- modest effect sizes may limit clinical relevance
- no long-term follow-up reported