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Title: 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
Author: Di Giandomenico, Silvana
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2012
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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 2nd 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 (MLS/RCLS) are characterized by the chromosomal translocation t(12;16) (q13; pI I), 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 In ML xenografts. The response to trabectedin in Type II xenografts was associated with partial regression and pathological response. Type III ML xenografts appeared less sensitive to trabectedin and tumors did not regress unless a more prolonged treatment is performed. 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 difference in sensitivity of type II and type III ML tumors to trabectedin is related to a difference in duration of the drug's ability to detach FUS-CHOP from DNA and that type III ML required more intensive and prolonged treatment to achieve a sufficient respond to trabectedin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.580639  DOI: Not available
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