Stacchiotti S, Saponara M, Frapolli R, Tortoreto M, Cominetti D, Provenzano S, Negri T, Dagrada G P, Gronchi A, Colombo C, Vincenzi B, Badalamenti G, Zuco V, Renne S L, Collini P, Morosi C, Dei Tos A P, Bello E, Pilotti S, Casali P G, D'Incalci M, Zaffaroni N
Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Medical Oncology Unit 2 (Adult Mesenchymal Tumours), Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Eur J Cancer. 2017 May;76:84-92. doi: 10.1016/j.ejca.2017.02.002. Epub 2017 Mar 8.
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.
模拟孤立性纤维瘤（SFT）病理和分子特征的临床前模型是选择有效治疗方案和待在临床中测试的新型化合物的重要工具。本研究旨在开发两种SFT临床前模型，评估其在临床中的预测价值，并选择潜在的新型有效治疗方法。
从患者活检组织中获得的两种去分化SFT（D-SFT）模型在免疫缺陷小鼠体内培养。测试了阿霉素、达卡巴嗪（DTIC）、异环磷酰胺（单药治疗或联合治疗）、曲贝替定和艾日布林对这些模型的抗肿瘤活性。12例SFT患者接受了阿霉素和DTIC治疗。通过实体瘤疗效评价标准（RECIST）评估反应、无进展生存期和总生存期，区分恶性SFT（M-SFT）和D-SFT。
开发并表征了两种源自D-SFT患者的异种移植瘤（PDX），它们代表了首个可用的SFT临床前体内模型。阿霉素/DTIC、DTIC/异环磷酰胺、阿霉素/异环磷酰胺联合用药始终比单药诱导出更好的抗肿瘤活性。特别是，阿霉素/DTIC联合用药在两种模型中均导致最大肿瘤体积抑制>80%。阿霉素/DTIC联合用药在病例系列中也显示出活性。最佳RECIST反应为：6例缓解（M-SFT为7例中的2例，D-SFT为5例中的4例），1例病情稳定，5例进展，中位无进展生存期为6个月（M-SFT为6个月，D-SFT为10个月）。PDX对曲贝替定和艾日布林非常敏感。
阿霉素加DTIC联合用药在我们的两种D-SFT小鼠模型中有效，在临床中似乎也有活性，尤其是在高级别D-SFT患者中。在PDX中测试的其他药物中，曲贝替定和艾日布林非常有效，为在D-SFT患者中测试这些药物提供了依据。
