Update on the role of trabectedin in the treatment of intractable soft tissue sarcomas

Recine, Federica; Bongiovanni, Alberto; Riva, Nada; Fausti, Valentina; Vita, Alessandro De; Mercatali, Laura; Liverani, Chiara; Miserocchi, Giacomo; Amadori, Dino; Ibrahim, Toni

doi:10.2147/ott.s127955

Cited by 29 publications

(24 citation statements)

References 69 publications

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“…The efficacy of this drug in STS, in particular the myxoid liposarcoma histotype, has been demonstrated in numerous clinical trials, but there are also reports of its activity in other sarcoma subtypes. 53 – 55 Although, there is limited evidence of the impact of trabectedin on MFS, 56 our results are suggestive of some activity in this STS subtype. Moreover, its antitumor activity appears to be related to its direct effect on both cancer cells and the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 60%

Myxofibrosarcoma primary cultures: molecular and pharmacological profile

et al. 2017

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Background:Myxofibrosarcoma (MFS), formerly considered as a myxoid variant of malignant fibrous histiocytoma, is the most common sarcoma of the extremities in adults and is characterized by a high frequency of local recurrence. The clinical behavior of MFS is unpredictable and the efficacy of chemotherapy is still not well documented. Furthermore, given the relatively recent recognition of MFS as a distinct pathologic entity its cellular and molecular biology has still not been extensively studied in patient-derived preclinical models. We examined the molecular biology and treatment outcomes of high-grade, patient-derived MFS primary cultures.Methods:A total of three patient-derived MFS primary cultures were analyzed. We evaluated the role of CD109 expression and also looked for a correlation between transforming growth factor-beta (TGF-β) expression and sensitivity of the primary cultures to different drugs.Results:CD109 was a promising marker for the identification of more aggressive high-grade MFS and a potential therapeutic target. The results also highlighted the potential role of TGF-β in chemoresistance. Pharmacological analysis confirmed the sensitivity of the cultures to chemotherapy. The most active treatments were epirubicin alone and epirubicin in combination with ifosfamide, the latter representing the current standard of care for soft tissue sarcomas (STSs), including MFS.Conclusions:Our results provide a starting point for further research aimed at improving the management of MFS patients undergoing chemotherapy.

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Section: Discussionmentioning

confidence: 60%

Myxofibrosarcoma primary cultures: molecular and pharmacological profile

et al. 2017

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“…We also investigated the efficacy of trabectedin, a marine-derived anticancer agent that has shown to improve the clinical outcome of patients with metastatic STS, especially liposarcomas and leiomyosarcomas (referred to as l -sarcomas in the literature) [ 30 , 31 ]. Trabectedin was approved in 2007 by the EMA, and in 2015 by the FDA, for the treatment of advanced STS after failure of anthracyclines or for disease not amenable to treatment with these agents [ 32 ]. In addition, we explored the efficacy of dacarbazine, a treatment option for metastatic STS (including UPS), which was used as control in a phase III trial evaluating eribulin efficacy in patients with advanced liposarcoma or leiomyosarcoma [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Primary Culture of Undifferentiated Pleomorphic Sarcoma: Molecular Characterization and Response to Anticancer Agents

Vita

Recine

Mercatali

et al. 2017

IJMS

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Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal neoplasm with no specific line of differentiation. Eribulin, a novel synthetic microtubule inhibitor, has shown anticancer activity in several tumors, including soft tissue sarcomas (STS). We investigated the molecular biology of UPS, and the mechanisms of action of this innovative microtubule-depolymerizing drug. A primary culture from a patient with UPS was established and characterized in terms of gene expression. The activity of eribulin was also compared with that of other drugs currently used for STS treatment, including trabectedin. Finally, Western blot analysis was performed to better elucidate the activity of eribulin. Our results showed an upregulation of epithelial mesenchymal transition-related genes, and a downregulation of epithelial markers. Furthermore, genes involved in chemoresistance were upregulated. Pharmacological analysis confirmed limited sensitivity to chemotherapy. Interestingly, eribulin exhibited a similar activity to that of standard treatments. Molecular analysis revealed the expression of cell cycle arrest-related and pro-apoptotic-related proteins. These findings are suggestive of aggressive behavior in UPS. Furthermore, the identification of chemoresistance-related genes could facilitate the development of innovative drugs to improve patient outcome. Overall, the results from the present study furnish a rationale for elucidating the role of eribulin for the treatment of UPS.

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“…Similar results were obtained by Bezdieniezhnykh et al who compared the effect of different anticancer drugs on primary cultures and corresponding established cell lines [ 44 ]. We treated IM-MFS-1 cells with MFS therapies of first and second line options including trabectedin, a marine-derived anticancer agent [ 24 , 26 , 45 ]. The primary culture, obtained by sample digestion (passage 1), was not particularly affected by any of the treatments ( Figure 5 A).…”

Section: Discussionmentioning

confidence: 99%

Characterization and Drug Sensitivity of a New High-Grade Myxofibrosarcoma Cell Line

Miserocchi

Vita

Mercatali

et al. 2018

Cells

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Myxofibrosarcoma (MFS) belongs to the group of sarcoma tumors, which represent only 1% of the totality of adult tumors worldwide. Thus, given the rare nature of this cancer, this makes the availability of MFS cell lines difficult. In an attempt to partially fill this gap, we immortalized a primary culture of MFS (IM-MFS-1) and compared the cell morphology with patient’s tumor tissue. IM-MFS-1 was genetically characterized through a Comparative Genomic Hybridization (CGH) array and the mesenchymal phenotype was evaluated using Polymerase chain reaction (PCR) and immunofluorescence staining. Drug sensitivity for MFS therapies was monitored over time in cultures. We confirmed the conservation of the patient’s tumor cell morphology and of the mesenchymal phenotype. Conversely, the synthesis and expression of CD109, a TGFβ co-receptor used to facilitate the diagnosis of high-grade MFS diagnosis, was maintained constant until high cancer cell line passages. The CGH array revealed a complex karyotype with cytogenetic alterations that include chromosome regions associated with genes involved in tumor processes. Cytotoxicity assays show drug sensitivity constantly increased during the culture passages until a plateau was reached. In conclusion, we established and characterized a new MFS cell line that can be used for future preclinical and molecular studies on soft tissue sarcomas.

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Update on the role of trabectedin in the treatment of intractable soft tissue sarcomas

Cited by 29 publications

References 69 publications

Myxofibrosarcoma primary cultures: molecular and pharmacological profile

Myxofibrosarcoma primary cultures: molecular and pharmacological profile

Primary Culture of Undifferentiated Pleomorphic Sarcoma: Molecular Characterization and Response to Anticancer Agents

Characterization and Drug Sensitivity of a New High-Grade Myxofibrosarcoma Cell Line

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