Trabectedin is a promising antitumor agent potentially inducing melanocytic differentiation for clear cell sarcoma

Abstract

Clear cell sarcoma is an aggressive soft tissue sarcoma and highly resistant to conventional chemotherapy and radiation therapy. This devastating disease is defined by EWSR1‐ATF1 fusion gene resulting from chromosomal translocation t(12;22)(q13;q12) and characterized by melanocytic differentiation. A marine‐derived antineoplastic agent, trabectedin, inhibits the growth of myxoid liposarcoma and Ewing sarcoma by causing adipogenic differentiation and neural differentiation, respectively. In this study, we examined the antitumor effects and mechanism of action of trabectedin on human clear cell sarcoma cell lines. We showed that trabectedin decreased the cell proliferation of five clear cell sarcoma cell lines in a dose‐dependent manner in vitro and reduced tumor growth of two mouse xenograft models. Flow cytometry and immunoblot analyses in vitro and immunohistochemical analysis in vivo revealed that trabectedin‐induced G2/M cell cycle arrest and apoptosis. Furthermore, trabectedin increased the expression of melanocytic differentiation markers along with downregulation of ERK activity in vitro and the rate of melanin‐positive cells in vivo. These results suggest that trabectedin has potent antitumor activity against clear cell sarcoma cells by inducing cell cycle arrest, apoptosis, and, in part, by promoting melanocytic differentiation through inactivation of ERK signaling. Our present study indicates that trabectedin is a promising differentiation‐inducing agent for clear cell sarcoma.

Myelolytic Treatments Enhance Oncolytic Herpes Virotherapy in Models of Ewing Sarcoma by Modulating the Immune Microenvironment

“…Trabectedin is a chemotherapeutic that has been previously shown to deplete tumor macrophages. 27 While trabectedin is currently FDA approved for liposarcoma, there is a growing body of preclinical research demonstrating therapeutic efficacy in Ewing sarcoma, 28 , 29 , 30 , 31 thought to be due to the interruption of the transcriptional activation by EWS-FLI1. For these reasons we sought to test the combination of trabectedin and oncolytic virus therapy against Ewing sarcoma.…”

Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model

“…TRAB has been demonstrated as a therapeutic option in STS [ 56 , 57 , 80 – 86 ], recurrent ovarian cancer [ 87 ], metastatic breast cancer [ 88 ], solitary fibrous tumor (SFT)-PDXs [ 89 ], desmoplastic small round cell tumor [ 90 ], juvenile myelomonocytic leukaemia and chronic myelomonocytic leukaemia [ 91 ]. Recently, we reported that TRAB is efficacious on an osteosarcoma cisplatinum-resistant lung metastasis [ 67 ], a BRAF-V600E mutated melanoma [ 30 , 32 ] and a gemcitabine (GEM)-resistant pancreatic cancer [ 25 ].…”

“…TRAB is a tetrahydroisoquinoline alkaloid compound, derived from the Carribean sea tunicate, Ecteinascidia turbinate [ 7 , 55 ]. TRAB is a promising antitumor agent [ 56 – 59 ]. Nteli et al [ 60 ] reported a durable response to TRAB in a patient with high-grade uterine leiomyosarcoma.…”

Marine natural products

“…688 The authors conclude the genes are "under strong purifying selection and are important to the symbiotic relationship". Trabectedin (ecteinascidin 743) exhibits in vitro and in vivo activity towards clear cell sarcoma cell lines, 689 while phase I trial data for plitidepsin (Aplidin®) in combination with sorafenib or gemcitabine shows them to be manageably safe with some objective responses observed. 690 Pharmacokinetic experiments with 14 C-plitidepsin show that 77.4% is excreted over 20 days, mainly in faeces, and that higher levels were detected in whole blood compared to plasma, indicating that red blood cells are the major distribution compartment.…”