S Stacchiotti1, M Saponara2, R Frapolli3, M Tortoreto4, D Cominetti4, S Provenzano2, T Negri5, G P Dagrada5, A Gronchi6, C Colombo6, B Vincenzi7, G Badalamenti8, V Zuco4, S L Renne9, P Collini9, C Morosi10, A P Dei Tos11, E Bello3, S Pilotti5, P G Casali12, M D'Incalci3, N Zaffaroni4. 1. Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Electronic address: silvia.stacchiotti@istitutotumori.mi.it. 2. Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 3. Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. 4. Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 5. Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 6. Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 7. Department of Oncology, University Campus Bio-Medico, via Alvaro del Portillo 21, Rome, Italy. 8. Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy. 9. 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. 10. Department of Radiology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 11. Department of Anatomic Pathology, General Hospital of Treviso, Treviso, Italy. 12. Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Oncology Department, University of Milan, Italy.
Abstract
BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: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: Tasuku Kiyuna; Yasunori Tome; Takashi Murakami; Kei Kawaguchi; Kentaro Igarashi; Kentaro Miyake; Masuyo Miyake; Yunfeng Li; Scott D Nelson; Sarah M Dry; Arun S Singh; Tara A Russell; Irmina Elliott; Shree Ram Singh; Fuminori Kanaya; Fritz C Eilber; Robert M Hoffman Journal: BMC Cancer Date: 2018-08-20 Impact factor: 4.430
Authors: Valentina Zuco; Sandro Pasquali; Silvia Stacchiotti; Nadia Zaffaroni; Monica Tortoreto; Silvia Brich; Stefano Percio; Gian Paolo Dagrada; Chiara Colombo; Roberta Sanfilippo; Calogero Lauricella; Mrinal Gounder; Rihan El Bezawy; Marta Barisella; Angelo Paolo Dei Tos; Paolo Giovanni Casali; Alessandro Gronchi Journal: J Exp Clin Cancer Res Date: 2021-03-01