Optimizing the Trabectedin Induced Differentiation of Ewing sarcoma Cells into Adipocytes

Background

Ewing’s sarcoma is the second most common pediatric bone tumor with a poor overall survival rate.  This tumor depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. Silencing of EWS-FLI1 is incompatible with the continued proliferation of Ewing’s sarcoma cells and places the cells in a de-differentiated state that clusters with mesenchymal stem cells by principle component analysis.  We have previously shown that treatment of Ewing’s sarcoma xenografts with trabectedin in combination with irinotecan leads to the differentiation and replacement of the tumor with fat; an effect that can be modeled in vitro. 

Project Goal

The goal of this study is to optimize this differentiation process in vitro by identifying a trabectedin analog with improved differentiation potential and/or combining the drug(s) with compounds such as rosiglitazone that are known to drive differentiation of mesenchymal stem cells into adipocytes.