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Published OnlineFirst November 25, 2013 .Conclusions:
These results provide the basis and rationale for translating this drug combination to the clinic. In addition, the study highlights an approach that utilizes a targeted agent to interfere with an oncogenic transcription factor and then exploits the resulting changes in gene expression to develop a molecularly targeted combination therapy.
Abstract :
Purpose: The goal of this study is to optimize the activity of trabectedin for Ewing sarcoma by developing a molecularly targeted combination therapy. Experimental Design: We have recently shown that trabectedin interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. In this report, we build on this work to develop a trabectedin based combination therapy with improved EWS-FLI1 suppression that also targets the drug associated DNA damage to ES cells.
Results: We demonstrate by siRNA experiments that EWS-FLI1 drives the expression of the Werner Syndrome protein (WRN) in ES cells. Since WRN deficient cells are known to be hypersensitive to camptothecins, we utilize trabectedin to block EWS-FLI1 activity, suppress WRN expression and selectively sensitize ES cells to the DNA damaging effects of SN38. We show that trabectedin and SN38 are synergistic, demonstrate an increase in DNA double strand breaks, an accumulation of cells in S-phase and a low picomolar IC50. In addition, SN38 cooperates with trabectedin to augment the suppression of EWS-FLI1 downstream targets, leading to an improved therapeutic index in vivo.
These effects translate into the marked regression of two Ewing sarcoma xenografts at a fraction of the dose of camptothecin used in other xenograft studies.
Copyright © 2013, American Association for Cancer Research.