April-Monn, Simon L; Kirchner, Philipp; Detjen, Katharina; Bräutigam, Konstantin; Trippel, Mafalda A; Grob, Tobias; Statzer, Cyril; Maire, Renaud S; Kollár, Attila; Chouchane, Aziz; Kunze, Catarina A; Horst, David; Sadowski, Martin C; Schrader, Jörg; Marinoni, Ilaria; Wiedenmann, Bertram; Perren, Aurel (2024). Patient derived tumoroids of high grade neuroendocrine neoplasms for more personalized therapies. NPJ precision oncology, 8(59) Springer Nature 10.1038/s41698-024-00549-2
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There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients' clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses.PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5 A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.
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