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Malignant pleural mesothelioma (MPM) incidence is increased over the past two decades and it is predicted to increase further in the next 20 years especially in developing countries where asbestos has not yet been banned. Surgery is not an option for the majority of patients due to the diffuse growth of MPM, making chemotherapy the treatment of choice, but prognosis remains very poor with a median survival time of 10-17 months. Trabectedin (ET-743, Yondelis) is a marine alkaloid used for the 2nd line therapy of ovarian cancer (combined with pegylated doxorubicin) and soft tissue sarcomas. It binds the DNA minor groove modulating transcription of cancer cells and has an anti-inflammatory effect modifying tumor microenvironment and reducing tumor associated macrophages. The aim was to test antitumor activity of trabectedin in newly established patient derived xenografts of MPM. MPM473, MPM484 and MPM487 xenografts were obtained in athymic nude mice by s.c. injection of 107 cells isolated from the pleural effusion of MPM patients and maintained by serial passages in mice. H&E staining and immunohistochemistry were performed. Mice were randomized when tumor reached about 200 mg to receive trabectedin, cisplatin, pemetrexed, gemcitabine, and imatinib. Antitumor activity was expressed as T/C% were T and C are the mean tumor weight of treated and control mice, respectively. The three xenografts reproduced the morphology and the histochemical profile of the human tumors. As reported in the table trabectedin was able to induce a 50% reduction in tumor growth in MPM473 and MPM 487 xenografts and only a marginal effect in MPM484 xenograft. TreatmentDose (mg/kg)ScheduleBest T/C% (Day)MPM473MPM484MPM487Cisplatin5i.v. q7dx361.9 (69)66.1 (69)67.3 (39)Gemcitabine100i.p. q4dx583.2 (41)67.7 (48)49.7 (56)Imatinib200p.o. qdx1568.9 (76)89.4 (55)87.1 (39)Pemetrexed250i.p. q4dx477.4 (52)76.8 (49)84.3 (39)Trabectedin0.15i.v. q7dx351.0 (73)63.6 (69)51.3 (56) In conclusion we report three new MPM xenografts able to mimic the pathological features of human MPM. Although trabectedin showed only a moderate antitumor activity in our experimental models, its efficacy is comparable or better than that of the other drugs currently used for this disease. Studies are in progress in syngenic models that are more appropriate to test also the ability of trabectedin to modulate the immune system. Citation Format: Simonetta Andrea Licandro, Roberta Frapolli, Ezia Bello, Roberta Libener, Sara Orecchia, Federica Grosso, Maurizio D’Incalci. Trabectedin activity in patient-derived mesothelioma xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3764.

Trabectedin (ET-743, Yondelis) is a marine alkaloid isolated from the tunicate Ecteinascidia turbinata, approved in Europe and US for the 2nd line therapy of soft tissue sarcomas. It is particularly effective against myxoid liposarcoma, a specific histological subtype within the family of adults soft tissue sarcomas. More than 90% of usual myxoid/round cell liposarcomas (MRCLS) are characterized by the chromosomal translocation t(12;16) (q13; p11), which produces the FUS-CHOP oncogene. Different chimera subtypes seem to respond differently to trabectedin in clinical setting. Trabectedin was able to remove FUS-CHOP type I, II and III from its own target genes but it causes adipocytic maturation and tumor regression only in type I and II, not in type III MRCLS (Di Giandomenico et al, Oncogene, 2014 Oct 30; 33(44): 5201-10). Pioglitazone is a PPARgamma agonist with pro-differentiation effects in different cancer types included liposarcomas (Tontonoz P. et al, Proc Natl Acad Sci U S A. 1997 Jan 7;94(1): 237-41). The aim of the study is to evaluate the efficacy of the combination of trabectedin with pioglitazone in type III myxoid liposarcoma xenografts. ML006 and ML004 type III MRCLS xenografts mice were treated with trabectedin 0.15 mg/kg iv every seven days for three times or pioglitazone 150 mg/kg po daily for 28 days or with their combination. For antitumor activity evaluation, tumor growth was measured with a caliper and the tumor weights (1 mm3 = 1 mg) were calculated with the formula: length × (width)2/2. Fifteen days after the last dose of trabectedin and 4 h after the last dose of pioglitazone tumors were collected from a separate group of mice to perform histological and molecular analyses. Trabectedin and pioglitazone as single agents have a comparable antitumor activity on these models with T/C around 40-50% with no tumor regression observed. In the combination groups an impressive and long lasting tumor regression was observed in ML 006 xenograft, with an observed optimal T/C of 17%. In ML004 MRCLS model the combination of trabectedin and pioglitazone induced a minimal regression followed by a long lasting tumor stabilization, resulting in a T/C of 23%. The histological analyses showed adipocytic maturation in tumors treated with pioglitazone alone or in combination but not in samples from mice treated with trabectedin alone. In conclusion, the combination of trabectedin with pioglitazone was able to induce tumor regression and adipocytic maturation in type III myxoid liposarcoma xenografts that were only marginally sensitive to trabectedin alone. Chromatin Immunoprecipitation, gene expression profile and Western Blot analysis are on-going to unravel the molecular mechanism behind the potentiation of the antitumor efficacy observed with this combination. Citation Format: Ezia Bello, Roberta Frapolli, Simonetta Andrea Licandro, Silvia Brich, Laura Carrassa, Roberta Sanfilippo, Alessandro Gronchi, Paolo Casali, Silvana Pilotti, Maurizio D’Incalci. PPARgamma agonist promotes adipocytic differentiation and potentiates the activity of trabectedin in myxoid liposarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1183.

Mesothelioma, sometimes referred to as asbestos cancer, is known to be among the most aggressive and difficult to treat tumours. The disease attacks the mesothelium, a protective two-layered membrane that covers the internal organs of the body including the lungs, heart and abdominal organs. Mesothelioma can affect any of these layers, but is usually seen in the pleural (lung) or peritoneal (abdomen) mesothelium. The most commonly diagnosed form of this cancer is pleural mesothelioma, caused primarily by the inhalation of asbestos fibers. The prevalence of this cancer is estimated at less than 1% of all cancers, however its incidence is increasing, with an expected peak in the next 10-20 years. Mesotheliomas are tumours that have a poor prognosis due to limited treatment options. The most aggressive form is the sarcomatoid histotype, followed by the biphasic and the epithelioid histotypes.In order to setup in vivo models of human mesothelioma, translational related to human pathology in terms of histology, antigen expression and pharmacological response to therapy, we have established three mesothelioma in vivo models using primary cells derived from patients having different mesothelioma histotypes.We stably transfected MM-432 (sarcomatoid), MM-473 (epithelioid) and MM-487 (biphasic) mesothelioma cell lines with a luciferase expression vector. The selected high luc-espressing clones were inoculated intrapleurally in immunodeficient nude mice, and they successfully invaded and proliferated within the murine host. In particular, the epithelioid histotype presented tumour growth 100% of the time, after a short latency period. The biphasic histotype failed to present tumour growth in 30% of the cases, however was far more aggressive than the epithelial histotype upon establishment of tumour growth. Moreover, the ex-vivo Immunocytochemistry (i.e for CEA, EMA, Mesothelin, Podoplanin, calretinin) and biochemical characterization (i.e.EGFR, VEGF, Top1, TKs pathways) of the three histotypes, revealed histotype-related differences. Finally, the cytotoxic responses to a panel of antitumor drugs (i.e . Doxorubicin , Topotecan , Ciclofosfamide, Dacarbazina, Gemcitabine, Temozolomide, Bortezomib, 5-azacitidina, Paclitaxel, Etoposide, 5-FU, Cisplatin, and AZD-2281) revealed that the three original cell lines, compared to the corresponding luc-expressing clones, had similar sensitivities to drugs depending upon the tumor histotypes. Further, in vivo characterizations focused on chemotherapeutic responses of these models, are currently in progress. Citation Format: Claudio Pisano, Alison G. Cole, Marcella Barbarino, Erminia Bianchino, Mario Guglielmi, Carmela Melito, Grazia Mercadante, Alfonsina Porciello, Assunta Riccio, Ilaria La Porta, Sara Orecchia, Roberta Libener, Laura Mazzucco, Simonetta Andrea Licandro, Pasquale De Luca. Mice models of three human mesothelioma histotypes derived from primary patient tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5556. doi:10.1158/1538-7445.AM2014-5556