Patient-derived tumoroids of advanced high-grade neuroendocrine neoplasms mimic patient chemotherapy responses and guide the design of personalized combination therapies
bioRxiv (Cold Spring Harbor Laboratory)(2022)
摘要
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 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 5A 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.
### Competing Interest Statement
The authors have declared no competing interest.
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关键词
tumoroids,mimic patient-derived chemotherapy responses,high-grade
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