Zebrafish Patient-Derived Xenograft Model to Predict Treatment Outcomes of Colorectal Cancer Patients

Abstract

The use of zebrafish embryos for personalized medicine has become increasingly popular. We present a co-clinical trial aiming to evaluate the use of zPDX (zebrafish Patient-Derived Xenografts) in predicting the response to chemotherapy regimens used for colorectal cancer patients. zPDXs are generated by xenografting tumor tissues in two days post-fertilization zebrafish embryos. zPDXs were exposed to chemotherapy regimens (5-FU, FOLFIRI, FOLFOX, FOLFOXIRI) for 48 h. We used a linear mixed effect model to evaluate the zPDX-specific response to treatments showing for 4/36 zPDXs (11%), a statistically significant reduction of tumor size compared to controls. We used the RECIST criteria to compare the outcome of each patient after chemotherapy with the objective response of its own zPDX model. Of the 36 patients enrolled, 8 metastatic colorectal cancer (mCRC), response rate after first-line therapy, and the zPDX chemosensitivity profile were available. Of eight mCRC patients, five achieved a partial response and three had a stable disease. In 6/8 (75%) we registered a concordance between the response of the patient and the outcomes reported in the corresponding zPDX. Our results provide evidence that the zPDX model can reflect the outcome in mCRC patients, opening a new frontier to personalized medicine.

Zebrafish xenograft as a tool for the study of colorectal cancer: a review

“…However, as many of these tumor lines exist and are readily available, it is important to choose the one more suitable for each research. While studies with a patient-derived approach are currently extremely infrequent [ 50 , 51 ], the vast majority of research has been performed on only a few CRC lines. The most commonly used, as can be observed in Fig.…”

Zebrafish Cancer Avatars: A Translational Platform for Analyzing Tumor Heterogeneity and Predicting Patient Outcomes

“…Several studies evaluated the ability of zPDX to predict patient responses (Table 3). A subset of these utilized a co-clinical trial design to implement a zebrafish avatar model [94,[118][119][120]. The concept of co-clinical trials arose from the increased understating of inter-tumoral heterogeneity, or the individuality of each patient's disease, and the need to optimize therapy at the patient level.…”

“…In addition, and under the same co-clinical trial, a zPDX avatar model was developed with samples from patients with colorectal cancer and used the adaptive RECIST criteria to predict chemotherapy response when treated with 5-FU, FOLFIRI, FOLFOX, FOLFOXIRI for two days. These zPDX avatars predicted chemotherapy response with 75% accuracy [119]. A similar trial is planned, called the Evaluation of Tumor Growth and Oncological Treatment in Patients With Colorectal Liver Metastases (CRLM) Using Zebra Fish Embryo Model (CRLM-Z) (clinicaltrials.gov identifier: NCT05289076).…”

“…Larval zebrafish PDX could address this issue. While the human cancer cells would still need to survive in a foreign tumor microenvironment, cells are xenografted into larvae directly from the primary tumor after dissociation into a single-cell suspension [68,83,92,94,95,119]. Experiments are completed within 5-10 days.…”

Combining preclinical tools and models to unravel tumor complexity: Jump into the next dimension

“…The use of multicellular organoids derived from minced tumor explants allows the conservation of the spatial distribution and architecture of the tissue, all aspects lost by enzymatic digestion processes. To further increase the complexity of the model, different groups demonstrate how the direct transplantation of patient's tissue fragments in zebrafish (ZF) embryos, named ZF "Avatars", can reflect the patient's outcome and could support co-clinical trials (18,19). It represents an additional step towards studies of precision medicine, but it seems unlikely to be applied to preclinical projects due the complex sample's characterization and the limited amount of material.…”