Open Access

ARTICLE

Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

Dina Polosukhina^*, Harold D. Love^*†, Harold L. Moses^‡§¶#, Ethan Lee^**††, Roy Zent^{†§**‡‡}, Peter E. Clark^*‡

* Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
† Department of Medicine (Nephrology and Hypertension), Vanderbilt University Medical Center, Nashville, TN, USA
‡ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
§ Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
¶ Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
# Department of Medicine (Hematology–Oncology), Vanderbilt University Medical Center, Nashville, TN, USA
** Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA
†† Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
‡‡ Veterans Affairs Hospital, Nashville, TN, USA

Oncology Research 2017, 25(9), 1653-1664. https://doi.org/10.3727/096504017X14992942781895

Abstract

Wilms tumor (WT) is the most common renal malignancy in children and the fourth most common pediatric solid malignancy in the US. Although the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/β-catenin pathway. We and others have shown that constitutive activation of β-catenin restricted to the renal epithelium is sufficient to induce primitive renal epithelial tumors, which resemble human WT. Here we demonstrate that pharmacologic inhibition of β-catenin gene transcription with pyrvinium inhibits tumor growth and metastatic progression in a murine model of WT. Cellular invasion is significantly inhibited in both murine WT-like and human WT cells and is accompanied by downregulation of the oncogenes Myc and Birc5 (survivin). Our studies provide proof of the concept that the canonical Wnt/β-catenin pathway may be a novel therapeutic target in the management of WT.

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