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Clin Cancer Res. 2014 Mar 1;20(5):1190-203. doi: 10.1158/1078-0432.CCR-13-0901. Epub 2013 Nov 25.

Dual targeting of EWS-FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth.

Author information

1
Authors' Affiliations: Monroe Carrell Jr. Children's Hospital at Vanderbilt and the Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Molecular Oncology Section, Pediatric Oncology Branch; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; and Istituto di Ricerche Farmacologiche "Mario Negri" -IRCCS, Milan, Italy.

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 Ewing sarcoma cells.

RESULTS:

We demonstrate by siRNA experiments that EWS-FLI1 drives the expression of the Werner syndrome protein (WRN) in Ewing sarcoma cells. Because WRN-deficient cells are known to be hypersensitive to camptothecins, we utilize trabectedin to block EWS-FLI1 activity, suppress WRN expression, and selectively sensitize Ewing sarcoma 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.

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.

PMID:
24277455
PMCID:
PMC5510643
DOI:
10.1158/1078-0432.CCR-13-0901
[Indexed for MEDLINE]
Free PMC Article

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