Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors

Claudia Forni, Mario Minuzzo, Emanuela Virdis, Elena Tamborini, Matteo Simone, Michele Tavecchio, Eugenio Erba, Federica Grosso, Alessandro Gronchi, Pierre Aman, Paolo Casali, Maurizio D'Incalci, Silvana Pilotti, Roberto Mantovani

Research output: Contribution to journalArticlepeer-review

Abstract

Differentiation is a complex set of events that can be blocked by rearrangements of regulatory genes producing fusion proteins with altered properties. In the case of myxoid liposarcoma (MLS) tumors, the causative abnormality is a fusion between the CHOP transcription factor and the FUS or EWS genes. CHOP belongs to and is a negative regulator of the large CAAT/enhancer binding protein family whose α, |β,and δ members are master genes of adipogenesis. Recent clinical data indicate a peculiar sensitivity of these tumors to the natural marine compound trabectedin. One hypothesis is that the activity of trabectedin is related to the inactivation of the FUS-CHOP oncogene. We find that trabectedin causes detachment of the FUS-CHOP chimera from targeted promoters. Reverse transcription-PCR and chromatin immunoprecipitation analysis in a MLS line and surgical specimens of MLS patients in vivo show activation of the CAAT/enhancer binding protein-mediated transcriptional program that leads to morphologic changes of terminal adipogenesis. The activity is observed in cells with type 1 but not type 8 fusions. Hence, the drug induces maturation of MLS lipoblasts in vivo by targeting the FUS-CHOP-mediated transcriptional block. These data provide a rationale for the specific activity of trabectedin and open the perspective of combinatorial treatments with drugs acting on lipogenic pathways.

Original languageEnglish
Pages (from-to)449-457
Number of pages9
JournalMolecular Cancer Therapeutics
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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