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

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. Clin Cancer Res; 21(6); 1373–82. ©2015 AACR.

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

“…S3). Trabectedin efficacy for ES was reported (25). Our results suggest similar treatment might be selected for CDS, however, it is ideal to develop treatment targeting CIC-DUX4 and related signaling pathways for precision medicine-based treatment.…”

“…Trabectedin is a Caribbean tunicate-extracted alkylating agent and is used for ovarian cancer and soft part sarcoma including leiomyosarcoma and liposarcoma (24, 25, 36, 37). Previous study reported that trabectedin exhibited growth inhibition of ES as a single agent, and improved effect in combination with an IGFR inhibitor (25). Therefore, trabectedin is a promising therapeutic agent for CDS despite lack of the synergistic effect with palbociclib.…”

CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

“…Our data suggest that combining IGF-1R inhibitors with anti-CD99 mAb may have an antagonistic effect. In contrast, CD99 triggering exploits the constitutive activation of the IGF-1R, which is sustained by EWS-FLI [49], and drives cells toward death.…”

Potential approaches to the treatment of Ewing's sarcoma

“…OSI-906 (linsitinib) greatly potentiates the efficacy of trabectedin in ES cells and mouse xenografts. ES patients also showed a preliminary response in a phase I study using OSI-906 [29, 30]. ADW742 inhibits ES cell proliferation and induces apoptosis.…”