Trabectedin efficacy in Ewing sarcoma is greatly increased by combination with anti-IGF signaling Agents.
Ana Teresa Monterio Amaral1, Cecilia Garofalo2, Roberta Frapolli3, Maria Cristina Manara4, Caterina Mancarella2, Sarah Uboldi5, Silvana Di Giandomenico6, José Luis Ordóñez7, Victoria Sevillano8, Roberta Malaguarnera9, Piero Picci10, Andrew Bassim Hassan11, Enrique De Alava8, Maurizio D'Incalci12, and Katia Scotlandi13,*
Link : http://clincancerres.aacrjournals.org/content/early/2015/01/21/1078-0432.CCR-14-1688.abstract
+ Author Affiliations
1Department of Pathology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), CSIC-Universidad de Sevilla
2Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli
3Oncology, Mario Negri Institute
4Laboratory of Experimental Oncology, Rizzoli Orthopaedic Institute
5Department of Oncology, Istituto Mario Negri
6Oncology, Istituto di Ricerche Farmacologiche Mario Negri- IRCCS
7MOLECULAR PATHOLOGY OF SARCOMAS, Instituto de Biomedicina de Sevilla (IBiS), CSIC-Universidad de Sevilla
8Department of Pathology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla-CSIC-Universidad de Sevilla. Hospital Universitario de Sevilla (IBiS-HUVR)
9Department of Health Sciences, University of Catanzaro
10Lab di Oncologia Sperimentale, Istituto Ortopedico Rizzoli
11Sir William Dunn School of Pathology, Oxford University
12Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri
13CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institu
Abstract :
Purpose:
Goal of this study was to identify mechanisms that limit efficacy of trabectedin (ET-743, YondelisTM) 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 (IGF-1R), and IGF-1 both in vitro and in xenografts treated with trabectedin or doxorubicin. Combined therapy with trabectedin and anti-IGF-1R 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 1 and type 2) 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 IGF-1R promoters, leading to IGF-1R up-regulation. Inhibition of IGF-1R either by the specific AVE1642 human antibody or by the dual IGF-1R/Insulin receptor inhibitor OSI-906 (Linsitinib) greatly potentiate the efficacy of trabectedin in the 13 Ewing sarcoma 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 thebinding of EWS-FLI1 to certain target genes, leading to up-regulation of IGF-1R. We here provide the rationale for combining trabectedin to anti-IGF-1R inhibitors.