# Patient-Derived Organoids from Pancreatic Neuroendocrine Tumors: A Systematic Review of PDO Take Rates, Molecular–Biological Characteristics, and Potential for Clinical Utility

## TL;DR

This study reviews patient-derived organoids from pancreatic neuroendocrine tumors, showing their potential for drug testing and personalized treatment despite challenges in consistency.

## Contribution

The paper provides a systematic review of PanNEN-derived organoids, highlighting their establishment success and translational potential for drug screening and biomarker discovery.

## Key findings

- PDOs were successfully generated from both PanNETs and PanNECs with an overall take rate of 75%.
- Drug screening revealed heterogeneous responses and identified novel therapeutic targets like EZH2 and Bcl-2.
- Variability in culture success and limited tissue availability emphasize the need for standardized protocols.

## Abstract

Pancreatic neuroendocrine neoplasia (PanNEN) consists of a set of rather rare and heterogeneous tumors, spanning from well-differentiated pancreatic neuroendocrine tumors (PanNETs) to poorly differentiated carcinomas (PanNECs). Therapeutic development has been limited by a lack of representative preclinical models. Patient-derived organoids (PDOs) represent a promising approach, preserving both histological and molecular features of the original tumors. In this systematic review, we summarize all published studies on PanNEN PDOs, including establishment success, validation strategies, culture longevity, and applications in drug testing. PDOs were successfully generated from both PanNETs and PanNECs, though take rates and culture durability varied. Drug screening studies highlighted inter-patient heterogeneity and uncovered potential novel therapeutic targets. Despite their promise, challenges such as variable culture success and limited tissue availability underscore the need for standardized protocols and prospective validation to fully realize their translational potential.

Background: Pancreatic neuroendocrine neoplasia (PanNEN) comprises a spectrum, from well-differentiated (i.e., G1, G2) pancreatic neuroendocrine tumors (PanNETs) to poorly differentiated carcinomas (PanNECs). Therapeutic progress is limited by the lack of representative preclinical models. Patient-derived organoids (PDOs) offer potential as translational models, but evidence remains scattered. Methods: We conducted a systematic review of PubMed (Jan 2009–Aug 2025) for original studies reporting on PDOs from PanNEN patients. Eligible studies were screened using the Rayyan software and data extracted from PDO take rates, validation methods, and clinical applications. Results: Twelve studies were included for qualitative and quantitative analyses. PDOs were successfully generated from both PanNETs (G1–G3; n = 26) and PanNECs (n = 6), primarily derived from primary tumors, but several studies also included metastatic sites. Take rates ranged from 33% to 100%, for a cumulative 33 PDOs from 44 attempts (overall take rate: 75%). Validation consistently employed histology, immunohistochemistry, and molecular profiling, with several studies incorporating xenotransplantation or omics approaches. PDOs demonstrated variable culture durations, from short-term (<3 weeks) to long-term (>20 passages). Drug screening studies (n = 7) revealed heterogenous responses to standard agents and pathways (everolimus, sunitinib, and temozolomide) and identified novel vulnerabilities, including EZH2 dependency, PI3K/CDK4/6 synergy, and Bcl-2-linked sensitivities in PanNECs. One study provided evidence of concordance between PDO drug sensitivity and patient responses. Conclusions: Research into PanNEN organoids remains limited. However, PDOs can preserve key histological and molecular features, enable pharmacotyping, and uncover candidate biomarkers for therapy. Despite feasibility across subtypes, progress is constrained by variability in culture success. Standardization and prospective validation are essential to advance PDOs as tools for personalized medicine in PanNENs.