title: Mode of action of trabectedin in myxoid liposarcomas.
abstract: To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro. Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Di Giandomenico
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Frapolli
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bello
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Uboldi
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: S A
authors.initials: SA
authors.lastname: Licandro
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marchini
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Beltrame
authors.affiliation: Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Brich
authors.affiliation: Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Mauro
authors.affiliation: Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Tamborini
authors.affiliation: Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Adult Sarcoma Medical Treatment Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Casali
authors.affiliation: Department of Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Grosso
authors.affiliation: Adult Sarcoma Medical Treatment Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Sanfilippo
authors.affiliation: Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gronchi
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Mantovani
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gatta
authors.affiliation: PharmaMar S.A., Madrid, Spain.
authors.forename: C M
authors.initials: CM
authors.lastname: Galmarini
authors.affiliation: PharmaMar S.A., Madrid, Spain.
authors.forename: J M F
authors.initials: JM
authors.lastname: Sousa-Faro
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000328:Adult; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001706:Biopsy; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004149:Dioxoles / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000188:drug therapy* / Q000235:genetics; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D015514:Oncogene Proteins, Fusion; D034702:RNA-Binding Protein FUS; C106030:TLS-CHOP fusion protein, human; D044005:Tetrahydroisoquinolines; D051742:Transcription Factor CHOP; D004317:Doxorubicin; D000077606:Trabectedin