title: Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour.
abstract: Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments.
  
  
  
  Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT.
  
  
  
  Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin.
  
  
  
  Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.
authors.affiliation: Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Electronic address: silvia.stacchiotti@istitutotumori.mi.it.
authors.forename: S
authors.initials: S
authors.lastname: Stacchiotti
authors.affiliation: Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Saponara
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: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tortoreto
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cominetti
authors.affiliation: Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Provenzano
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Negri
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: G P
authors.initials: GP
authors.lastname: Dagrada
authors.affiliation: Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gronchi
authors.affiliation: Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Department of Oncology, University Campus Bio-Medico, via Alvaro del Portillo 21, Rome, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Vincenzi
authors.affiliation: Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Badalamenti
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Zuco
authors.affiliation: Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: S L
authors.initials: SL
authors.lastname: Renne
authors.affiliation: Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Collini
authors.affiliation: Department of Radiology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Morosi
authors.affiliation: Department of Anatomic Pathology, General Hospital of Treviso, Treviso, Italy.
authors.forename: A P
authors.initials: AP
authors.lastname: Dei Tos
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: Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Oncology Department, University of Milan, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Casali
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003606:Dacarbazine / Q000008:administration & dosage; D004149:Dioxoles / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005663:Furans / Q000008:administration & dosage; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007659:Ketones / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016513:Mice, SCID; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality; D066066:Response Evaluation Criteria in Solid Tumors; D012186:Retroperitoneal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D012189:Retrospective Studies; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000401:mortality; D054364:Solitary Fibrous Tumors / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage; D000077606:Trabectedin; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D003606:Dacarbazine; D004149:Dioxoles; D004317:Doxorubicin; D005663:Furans; D007069:Ifosfamide; D007659:Ketones; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; C490954:eribulin; D000095662:Polyether Polyketides
keywords: Anthracycline; Chemotherapy; Dacarbazine; Doxorubicin; Eribulin; Ifosfamide; Metastasis; Mice model; Sarcoma; Solitary fibrous tumour; Trabectedin; Treatment; Xenograft