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Transplantation of Zebrafish Pediatric Brain Tumors into Immune-competent Hosts for Long-term Study of Tumor Cell Behavior and Drug Response
Published on: May 17, 2017
Modeling High-Risk Pediatric Cancers in Zebrafish to Inform Precision Therapy
Nadine Azzam1, Jamie I Fletcher2,3, Nicole Melong1
1Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
Abstract:
Despite advances in precision medicine, 30% of high-risk pediatric cancers lack an actionable molecular target, hindering effective treatment and affecting survival outcomes. Although mouse patient-derived xenograft (PDX) models offer additional insights into clinical drug responses, delivering findings from these models within a clinically actionable time frame remains challenging. This international collaboration between two national precision medicine programs demonstrates proof-of-principle that individualized larval zebrafish PDXs can robustly and rapidly assess clinical responses in high-risk pediatric cancers. Retrospective zebrafish PDX testing was performed on tumor samples from 10 pediatric patients with high-risk cancers. Drug responses in zebrafish models were correlated with clinical responses for each patient and directly compared with responses in cognate mouse PDX models. Responses to conventional and targeted therapies, administered as single agents or in combinations, were assessed. Zebrafish PDXs were successfully established from all 10 patients and provided robust drug response data in every case, including from three patients whose tumor samples could not be engrafted in mice. Remarkably, zebrafish models accurately recapitulated patient responses for 11 of 12 treatment regimens. These findings highlight the potential of larval zebrafish PDX models to provide real-time, clinically relevant drug response data, supporting their potential use in prospective precision medicine studies.
Significance:
This proof-of-principle study is the first to compare drug responses in larval zebrafish and mouse PDX models with patient outcomes in pediatric precision oncology, showing high concordance. Results highlight the potential of zebrafish PDX models to predict drug responses in high-risk cancers more accurately, rapidly, and cost-effectively in prospective studies.
Insights
Larval zebrafish patient-derived xenografts (PDXs) rapidly and accurately predict pediatric cancer drug responses. This approach offers a faster, more cost-effective alternative to mouse PDXs for precision oncology.
Area of Science:
- Pediatric Oncology
- Translational Medicine
- Xenograft Models
Background:
- 30% of high-risk pediatric cancers lack actionable molecular targets, limiting treatment options.
- Mouse patient-derived xenograft (PDX) models show promise but face challenges in timely clinical application.
- There is a critical need for rapid and reliable drug response prediction in pediatric precision oncology.
Purpose of the Study:
- To demonstrate the proof-of-principle for using individualized larval zebrafish PDX models to rapidly assess clinical drug responses in high-risk pediatric cancers.
- To compare the efficacy of zebrafish PDX models against conventional mouse PDX models in predicting patient outcomes.
- To evaluate the potential of zebrafish PDXs for real-time, clinically relevant drug response data generation.
Main Methods:
- Retrospective analysis of tumor samples from 10 pediatric patients with high-risk cancers.
- Establishment and drug response testing of larval zebrafish PDX models.
- Correlation of zebrafish PDX drug responses with patient clinical responses and comparison with mouse PDX models.
- Assessment of responses to single-agent and combination therapies.
Main Results:
- Zebrafish PDXs were successfully established from all 10 patients, yielding robust drug response data in every case.
- Zebrafish models provided data for three patients whose tumors failed to engraft in mice.
- Zebrafish PDX models accurately recapitulated patient responses for 11 out of 12 treatment regimens tested.
- High concordance was observed between zebrafish PDX, mouse PDX, and patient outcomes.
Conclusions:
- Individualized larval zebrafish PDX models offer a robust, rapid, and cost-effective platform for predicting drug responses in high-risk pediatric cancers.
- Zebrafish PDX models demonstrate significant potential for improving precision medicine strategies in pediatric oncology.
- These findings support the prospective use of zebrafish PDX models to guide clinical treatment decisions in real-time.
