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posted on 2025-07-25, 08:40 authored by Nadine Azzam, Jamie I. Fletcher, Nicole Melong, Loretta M.S. Lau, Emmy M. Dolman, Jie Mao, Gabor Tax, Roxanne Cadiz, Lissandra Tuzi, Alvin Kamili, Biljana Dumevska, Jinhan Xie, Jennifer A. Chan, Donna L. Senger, Stephanie A. Grover, David Malkin, Michelle Haber, Jason N. Berman <p>Mouse and larval zebrafish PDX drug efficacy for responsive patients. <b>A to D,</b> Patient information, alongside mouse PDX waterfall plot of maximum tumor regression, and larval zebrafish tumor cell numbers for each therapy for Ewing sarcoma zccs505 (<b>A</b>), anaplastic large cell lymphoma zccs250 (<b>B</b>), neuroblastoma zccs51 (<b>C</b>), and Ewing sarcoma zccs59 (<b>D</b>). For mouse PDX data, colored columns represent individual mice. For larval zebrafish data, error bars represent mean ± SEM, each colored dot represents an individual larva, and a threshold is based on SEM of 1 dpi. Statistical analysis was conducted using a one-way ANOVA with the Dunnett multiple comparisons test, comparing the mean of each treatment group with control (4 dpi), <i>P</i> values: *, < 0.05; **, < 0.01; ***, < 0.001; ****, < 0.0001. Treatments are ordered and colored the same in mouse and zebrafish studies. mut, mutant; dpi, days post-injection.</p>
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ARTICLE 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.
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.
