Prediction of Sensitivity and Efficacy of Clinical Chemotherapy Using Larval Zebrafish Patient-Derived Xenografts of Gastric Cancer

Abstract

Background: Perioperative chemotherapy has been accepted as one of the most common approaches for locally advanced gastric cancer. However, the efficacy of chemotherapy varies among patients, and there is no effective method to predict the chemotherapy efficacy currently. We previously established the first larval zebrafish patient-derived xenografts (zPDXs) of gastric cancer as a platform for the translational research and personalized treatment. The objective of this study was to investigate the feasibility of screening individualized chemotherapeutics using the zPDXs. Methods: We further optimized this zPDXs platform including administration route, drug dosing, and rhythm to develop a stable and reliable protocol for chemotherapeutics screening. Using the novel platform, we investigated the chemosensitivity of 5-fluorouracil, cisplatin, docetaxel, and doxorubicin for gastric cancer patients. Results: We showed that the engrafted zebrafish retained the original prominent cell components of the corresponding human tumor tissues, and we successfully obtained the results of chemosensitivity of 5-fluorouracil, cisplatin, docetaxel, and doxorubicin for 28 patients with locally advanced gastric cancer. These patients underwent radical gastrectomy for curative intent and 27 cases received postoperative adjuvant chemotherapy. We revealed that the chemosensitivity obtained from zPDXs was consistent with the clinical responses in these patients (P = 0.029). More importantly, the responder drug(s) from zPDXs used or not was the only risk factor for early-stage recurrence in these 27 patients (P = 0.003). Conclusion: Our study with the largest sample size so far suggests that larval zPDXs help to predict the chemotherapeutics response and to achieve precise chemotherapy for gastric cancer.