Mode of Action of Trabectedin in Human Mixoid Liposarcoma Growing in Immunodeficient Mice: Evidence that the Drug Acts by Displacing FUS-CHOP Chimeric Protein From its Target Promoters

Di Giandomenico, Silvana (2012). Mode of Action of Trabectedin in Human Mixoid Liposarcoma Growing in Immunodeficient Mice: Evidence that the Drug Acts by Displacing FUS-CHOP Chimeric Protein From its Target Promoters. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f0af

Abstract

Trabectedin (ET-743, Yondelis) is a marine alkaloid isolated from the tunicate Ecteinascidia turbinata, cytotoxic against a variety of tumor cell lines in vitro and human tumor xenografts in vivo. It has been approved by EMEA for the 2nd line therapy of soft tissue sarcomas in 2007 and for the 2 line therapy of ovarian cancer in 2009. Myxoid liposarcoma (ML) is a specific histological subtype within the family of adults soft tissue sarcomas. Specifically >90% of usual myxoid/round cell liposarcomas (ML/RCLS) are characterized by the chromosomal translocation t(12;16) (q13; p11), which produces the FUS-CHOP oncogene. Different chimera subtypes seem to respond differently to trabectedin in clinical setting. To elucidate the mechanisms behind the differential sensitivity to trabectedin, tumor myxoid liposarcomas type II and type III were xenografted in nude mice, treated with trabectedin (0.15 mg/kg was injected i.v.) and the binding of FUS-CHOP to some of its target promoters was monitored by Chromatin immuno precipitation to verify the drug ability to displace the binding. We found that trabectedin was more effective on type II than type III ML xenografts. The response to trabectedin in Type II xenografts was associated with partial regression and pathological response. Type III ML xenografts appeared much less sensitive to trabectedin and tumors did not regress. Molecular analysis revealed that trabectedin was able to remove FUS-CHOP type II and III from its own gene targets 24 hours after treatment. 72 hours after treatment, FUS-CHOP Type III was attached to its targets whereas FUS-CHOP Type II remained unbound. The results suggest that the different of type II and type III to trabectedin are related to a different duration of the drug ability to display FUS-CHOP from DNA.