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

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 A, B,and D 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. [Mol Cancer Ther 2009;8(2):449 -57]

Detection and characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts)

“…Preliminary studies have suggested that myxoid liposarcomas with type I FUS-CHOP chimeric transcript may respond better to trabectedin. 37,38 Although the role of chimeric transcript type and variants have not been established in clear cell sarcoma, future studies or new therapeutic approaches may be revealing.…”

Detection of myxoid liposarcoma-associated FUS–DDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay

“…One variant may be more aggressive than the others, or may respond better to chemotherapy such as trabectedin. 2,12,15,16 As newer chemotherapeutic and other treatment strategies are developed for myxoid liposarcoma, confirmation of both the diagnosis and subtyping of the translocation may become part of routine clinical practice and of future research studies to identify the best treatment for each patient in this era of personalized medicine. In conclusion, we have developed a clinically robust RT-PCR assay that can identify and determine all known breakpoints in the most common subtypes of myxoid liposarcoma, and have identified a new FUS-DDIT3 mRNA breakpoint, which needs to be considered in future myxoid liposarcoma studies.…”

“…15 In addition, an in vitro study of the drug on myxoid liposarcoma cell lines showed that treatment with trabectedin lead to dissociation of the FUS-DDIT3 protein product from chromatin and promotes gene expression consistent with terminal adipogenesis, but this response was only seen in the cell lines with the type 1 FUS-DDIT3 fusion and not in a cell line with the rarer type 8 gene fusion. 16 Of note, both the type 3 and type 8 gene fusions have more of the RNAbinding domain from FUS included in the gene fusion. Although these data are incomplete, it suggests that as new therapies are developed, the specific gene fusion type may become relevant, which highlights the need for assays that can differentiate the gene fusion type in the clinical setting.…”

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

“…Moreover, trabectedin treatment was associated with significant histopathologic changes, characterized by regression of the capillary network and a presence of mature lipoblasts. A possible explanation for these changes could be that, by blocking the trans-activating ability of FUS-CHOP chimeric protein, trabectedin might modulate the transcription of genes that are crucial for adipocytic differentiation (28). The findings observed in myxoid liposarcoma could also be extrapolated to other sarcomas in which the translocation results in an altered regulation of the expression of transcription factors.…”