INHIBITION OF WILMS TUMOR XENOGRAFT PROGRESSION BY HALOFUGINONE IS ACCOMPANIED BY ACTIVATION OF WT-1 GENE EXPRESSION

Abstract

Wilms tumor (WT) is the most common malignant neoplasm of the urinary tract in children. Although it is curable with long-term survival, the combination of surgery, chemotherapy and often radiotherapy in some cases results in severe complications in adulthood. Therefore, novel therapeutic strategies that would decrease treatment burden and improve outcome for high risk patients are required. We evaluated the efficacy of halofuginone, an inhibitor of collagen type I synthesis and angiogenesis, to inhibit WT development in xenografts models. WTs derived from 2 patients with favorable histology at different disease stages were implanted subcutaneously or orthotopically in the kidneys of nude mice. Halofuginone was administered intraperitoneally (2 mug per mouse every other day) or given in the diet (1 part per million). Independent of disease stage, tumor location or administration route, halofuginone caused a decrease in angiogenesis that resulted in marked inhibition of tumor development. This result was accompanied by a reduction in collagen synthesis, reduced levels of hepatocyte growth factor receptor MET and increased levels of the tumor suppressor protein WT1. In culture halofuginone increased the synthesis of WT1 in the human WT cell-line SK-NEP-1 and in other cancer cell lines such as hepatocellular carcinoma and prostate cancer. In SK-NEP-1 halofuginone also lowered erb B2 levels and reduced cell proliferation. These results suggest that halofuginone is a potent inhibitor of WT progression. Because of its unique mode of action, halofuginone may decrease the treatment burden when combined with chemotherapy.