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Trabectedin Efficacy in Ewing Sarcoma Is Greatly Increased by Combination with Anti-IGF Signaling Agents.

Amaral AT1, Garofalo C2, Frapolli R3, Manara MC2, Mancarella C2, Uboldi S3, Giandomenico SD3, Ordóñez JL1, Sevillano V1, Malaguarnera R4, Picci P2,Hassan AB5, Alava ED1, D’Incalci M3, Scotlandi K6. Clin Cancer Res. 2015 Mar 15;21(6):1373-82.

Show Affiliations

1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Department of Pathology, Seville, Spain.

2Experimental Oncology Lab, CRS Development of Biomolecular Therapies, Rizzoli Institute, Bologna, Italy.

3Department of Oncology IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

4Department of Health, University of Catanzaro, Catanzaro, Italy.

5Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.

6Experimental Oncology Lab, CRS Development of Biomolecular Therapies, Rizzoli Institute, Bologna, Italy. [email protected]

 

Abstract

PURPOSE:

Goal of this study was to identify mechanisms that limit efficacy of  trabectedin  (ET-743, Yondelis) in Ewing sarcoma (EWS), so as to develop a clinical applicable combination therapy.

EXPERIMENTAL DESIGN:

By chromatin immunoprecipitation, we analyzed EWS-FLI1 binding to the promoters of several target genes, such as TGFβR2, CD99, insulin-like growth factor receptor 1 (IGF1R), and IGF1, both in vitro and in xenografts treated with trabectedin or doxorubicin. Combined therapy with trabectedin and anti-IGF1R agents (AVE1642 HAb; OSI-906) was tested in vitro and in xenografts.

RESULTS:

We confirm that both trabectedin and doxorubicin were able to strongly reduce EWS-FLI1 (both type I and type II) binding to two representative target genes (TGFβR2 and CD99), both in vitro and in xenografts. However, trabectedin, but not doxorubicin, was also able to increase the occupancy of EWS-FLI1 to IGF1R promoters, leading to IGF1R upregulation. Inhibition of IGF1R either by the specific AVE1642 human antibody or by the dual IGF1R/insulin receptor inhibitor OSI-906 (Linsitinib) greatly potentiate the efficacy of trabectedin in the 13 EWS cell lines here considered as well as in TC-71 and 6647 xenografts. Combined therapy induced synergistic cytotoxic effects. Trabectedin  and OSI-906 deliver complementary messages that likely converge on DNA-damage response and repair pathways.

CONCLUSIONS:

We showed that trabectedin may not only inhibit but also enhance the binding of EWS-FLI1 to certain target genes, leading to upregulation of IGF1R. We here provide the rationale for combining trabectedin to anti-IGF1R inhibitors.

©2015 American Association for Cancer Research.

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Figure Legend

Schematic representation of trabectedin activity in EWS. Trabectedin may not only inhibit (1) but also enhance the binding of EWS-FLI1 to target genes. Specifically, IGF-1R expression is activated after treatment with trabectedin (3), therefore providing the rationale for combined treatments with anti-IGF-1R agents. Reprinted with permission from the American Association for Cancer Research (Clin Cancer Res. 2015 Mar 15;21(6):1373-82. doi: 10.1158/1078-0432.CCR-14-1688.)

 

Trabectedin efficacy in Ewing sarcoma is greatly increased by combination with anti-IGF signaling agents.. Global Medical Discovery