A New Strategy for Screening Effective Therapies for Metastatic Wilms Tumors

PROJECT SUMMARY Wilms tumor (WT) is the second most common solid pediatric cancer that usually develops in young children before age 5. WT encompass three main cell types: epithelium, stroma, and blasterma. WT are typically treated with a combination of surgery, chemotherapy and radiotherapy. Although the survival rate for WT

patients is generally favorable, prognosis for patients with blastema dominant histology remain poor. Patients with blastema dominant histology are more resistance to chemotherapy and have higher rate of cancer recurrence, therefore there is unmet clinical need to improve therapy. The major obstacle for developing

novel therapies is the lack of cell lines and animal models representing high-risk blastemal WT. Because blastemal WT represents aberrant ESCs, we reprogrammed WiT49 WT cells of epithelial origin into induced pluripotent stem cells (iPSCs) and transplanted iPSCs into kidneys of mice. The tumors metastasized to the

liver and lung. Thus, WiT49-iPSCs represent the first blastemal WT model suitable for mechanistic studies to understand the molecular changes distinguishing epithelial and blastemal types of WT and can be used to screen FDA-approved drugs to find better treatments for children with aggressive WT. Because WiT49-iPSCs

acquire stem cell markers as well as metastatic traits as compared to WiT49, we hypothesize that WiT49- iPSCs serve as a blastemal WT model suitable for mechanistic studies and drug screening to develop novel therapies for metastatic blastemal WT. In this proposed study, we will (1) reprogram WiT49-iPSCs and

perform the teratoma assay to determine stem cell potency. (2) identify the epigenetic and chromatin signatures distinguishing the blastemal and epithelial types of WT. (3) develop novel therapeutic strategies for the treatment of WT. We will screen WiT49 and WiT49-iPSC cells against FDA-approved drugs and

epigenetic compounds to identify drugs effective against WiT49-iPSCs versus WiT-49 cells. Successful completion of this project is expected to have a great impact on understanding the biology of kidney cancer and establishing the invaluable experimental platform for the development of safer and more effective

therapies for Wilms tumors.