Clinical and translational medicine · 2025
Organoid-based two-step drug screening for rapid identification of chemotherapy-resistant oesophageal squamous cell carcinoma and alternative therapies.
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Shao Chen-Ye, Ju Sheng, Tong Xin, Hu Kang, Li Yu, Zhu Yi-Xian, Yang Jian, Li Chang, Xie Yu-Feng, Cui Yuan, Deng Wei-Jun, Ding Cheng, Qin Song-Bing, Zhao Jun
Аннотация
BACKGROUND: Despite guideline-directed therapies, most patients with advanced oesophageal squamous cell carcinoma (ESCC) derive limited benefit and are unable to tolerate iterative treatment modifications. Therefore, timely identification of resistant cases and the provision of alternative therapeutic options are urgently needed.
METHODS: A large-scale patient-derived organoid model was established from locally advanced patients with ESCC who underwent perioperative chemotherapy and was validated for consistency with the parental tumours through histopathological, genomic and transcriptomic analysis. A novel two-step drug screening method based on growth rate inhibition (GR) was developed, and drug sensitivity results were compared with clinical outcomes. Additionally, in vivo assays were conducted to evaluate alternative therapies using the Cmax/GR100 index.
RESULTS: ESCC organoids demonstrated high consistency with parental tumours in histopathology, genomics and transcriptomics. The two-step drug screening method revealed a strong correlation with clinical responses (sensitivity 80%, specificity 85.7%, overall accuracy 83.3%) and significantly shortened the experimental timeline compared with the traditional drug screening method (23.08 ± 2.42 days vs. 45.75 ± 7.19 days, p < .001). Furthermore, we proposed a novel drug selection strategy based on Cmax/GR100 values, which provides a theoretical foundation for drug repurposing and offers alternative treatment options for patients resistant to TP (taxol + cisplatin) therapy, thereby facilitating precise re-treatment in drug-resistant subgroups.
CONCLUSIONS: This method exhibits strong clinical applicability, supporting more accurate and timely decision-making in ESCC management. The Cmax/GR100-based drug screening strategy can dynamically identify alternative sensitive drugs for patients who fail first-line therapies, enabling precise re-treatment. This approach provides a valuable tool for translating laboratory findings into clinical practice.
METHODS: A large-scale patient-derived organoid model was established from locally advanced patients with ESCC who underwent perioperative chemotherapy and was validated for consistency with the parental tumours through histopathological, genomic and transcriptomic analysis. A novel two-step drug screening method based on growth rate inhibition (GR) was developed, and drug sensitivity results were compared with clinical outcomes. Additionally, in vivo assays were conducted to evaluate alternative therapies using the Cmax/GR100 index.
RESULTS: ESCC organoids demonstrated high consistency with parental tumours in histopathology, genomics and transcriptomics. The two-step drug screening method revealed a strong correlation with clinical responses (sensitivity 80%, specificity 85.7%, overall accuracy 83.3%) and significantly shortened the experimental timeline compared with the traditional drug screening method (23.08 ± 2.42 days vs. 45.75 ± 7.19 days, p < .001). Furthermore, we proposed a novel drug selection strategy based on Cmax/GR100 values, which provides a theoretical foundation for drug repurposing and offers alternative treatment options for patients resistant to TP (taxol + cisplatin) therapy, thereby facilitating precise re-treatment in drug-resistant subgroups.
CONCLUSIONS: This method exhibits strong clinical applicability, supporting more accurate and timely decision-making in ESCC management. The Cmax/GR100-based drug screening strategy can dynamically identify alternative sensitive drugs for patients who fail first-line therapies, enabling precise re-treatment. This approach provides a valuable tool for translating laboratory findings into clinical practice.