A57
Trabectedin (ET-743) is a pro-differentiation drug in myxoid liposarcoma tumors
Claudia Forni1, Mario Minuzzo1, Emanuela Virdis2, Elena Tamborini2, Matteo Simone3, Michele Tavecchio3, Eugenio Erba3, Federica Grosso2, Alessandro Gronchi2, Pierre Aman4, Paolo Casali2, Maurizio D'Incalci3, Silvana Pilotti2, Roberto Mantovani1
1Università degli Studi di Milano, Milan, Italy, 2Istituto Nazionale Tumori, Milan, Italy, 3Istituto Mario Negri, Milan, Italy, 4Göteborg University, Göteborg, Sweden
Differentiation is a complex set of events that leads to the exit from the cell-cycle and the acquisition of specific cellular features; in certain pathways, this process 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 C/EBP 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.
Here, we find that Trabectedin causes a specific post-transcriptional elimination of the FUS-CHOP chimaera. RT-PCR and ChIP analysis in MLS lines and surgical specimens of MLS patients in vivo show activation of the C/EBP-mediated transcriptional program that leads to morphologic changes of terminal adipogenesis.
Hence, the drug induces maturation of MLS lipoblasts in vivo by targeting the FUS-CHOP-mediated transcriptional block. Those data provide a rationale for the specific activity of Trabectedin and open the perspective of combinatorial treatments with drugs acting on lipogenic pathways.
