Advanced

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

Forni, Claudia; Minuzzo, Mario; Virdis, Emanuela; Tamborini, Elena; Simone, Matteo; Tavecchio, Michele LU ; Erba, Eugenio; Grosso, Federica; Gronchi, Alessandro and Aman, Pierre, et al. (2009) In Molecular Cancer Therapeutics 8(2). p.57-449
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 alpha, beta, and delta 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... (More)

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 alpha, beta, and delta 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.

(Less)
Please use this url to cite or link to this publication:
@article{27288127-a428-411f-afd2-f0e6b688b722,
  abstract     = {<p>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 alpha, beta, and delta 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.</p>},
  author       = {Forni, Claudia and Minuzzo, Mario and Virdis, Emanuela and Tamborini, Elena and Simone, Matteo and Tavecchio, Michele and Erba, Eugenio and Grosso, Federica and Gronchi, Alessandro and Aman, Pierre and Casali, Paolo G and D'Incalci, Maurizio and Pilotti, Silvana and Mantovani, Roberto},
  issn         = {1535-7163},
  keyword      = {Adipogenesis,Antineoplastic Agents,Apoptosis,Biomarkers, Tumor,CCAAT-Enhancer-Binding Protein-beta,Cell Differentiation,Cell Line, Tumor,Dioxoles,Drug Screening Assays, Antitumor,Female,Gene Expression Regulation, Neoplastic,Humans,Liposarcoma, Myxoid,Male,Middle Aged,Oncogene Proteins, Fusion,Protein Binding,RNA-Binding Protein FUS,Tetrahydroisoquinolines,Transcription Factor CHOP,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {2},
  pages        = {57--449},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Therapeutics},
  title        = {Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors},
  url          = {http://dx.doi.org/10.1158/1535-7163.MCT-08-0848},
  volume       = {8},
  year         = {2009},
}