Abstract
The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.
Highlights
The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes
For 5–7% of WT patients who present with synchronous bilateral disease, current treatment protocols mandate neoadjuvant chemotherapy followed by surgical resection, most often in the form of bilateral nephron-sparing surgery
Percentage of the same CN status histology WT (TP53 mutation and/or 17p loss) and models of WT with propensity for disease relapse that have not been previously captured by genetically engineered mouse models or cell lines
Summary
The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes. Despite the overall success in treatment achieved by large-scale cooperative trials conducted over the last 40 years, patients with unfavorable histology WT (diffuse anaplasia), disease relapse, or bilateral tumors (stage V) continue to have suboptimal outcomes[2]. Tumors with diffuse anaplasia were found to be resistant to vincristine, actinomycin-D, and doxorubicin, chemotherapy drugs which constitute the mainstay of therapy for most favorable histology disease[6]. The rate of end stage renal disease related to treatment of BWT is 14%
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