Patient-derived tumoroids of advanced high-grade neuroendocrine neoplasms mimic patient chemotherapy responses and guide the design of personalized combination therapies

Abstract

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous epithelial malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and used this model for targeted ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug sensitivity 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 5A and interferon-beta, which act synergistically in combination with cisplatin. Since rapid ex vivo drug screens in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.

Models in Pancreatic Neuroendocrine Neoplasms: Current Perspectives and Future Directions

“…Finally, drug screening applications were demonstrated using paclitaxel, everolimus, and navitoclax, demonstrating the suitability of these PTOs for this application. The second preprint demonstrated the continued work of April-Monn et al on tumoroids [177]. The group would create three new PTO sets from pNEN tissues, although a rigorous preselection process was performed beforehand.…”

“…Advances in gene editing, including CRISPR/Cas9, have been utilized in both cell and in frog models of pNENs, creating new molecular model subtypes of previously existing models [36,161,202]. Coupled with more advanced maintenance and establishment techniques, new cell lines and 3D models have shown to be more accurate representations of pNENs than earlier established methods [57,177]. Three-dimensional models are especially promising, creating an accurate tumor model while combining the high-throughput capabilities of cell lines.…”