title: Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro.
abstract: Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or nonadherent spheroids with IC50values ≤ 2.6 nmol/L. Nonmalignant mesothelial cells were significantly less responsive. The strong antimesothelioma activity was based on cell-cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by coadministration of cisplatin, a drug routinely used for systemic MPM treatment. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl-2 expression. Accordingly, bcl-2 inhibitors (Obatoclax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bcl-2, bim, bax, Mcl-1, and bcl-xLas a consequence of trabectedin exposure. In addition, trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Together, these data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors in vitro Thus, it represents a promising new therapeutic option for MPM. Mol Cancer Ther; 15(10); 2357-69. ©2016 AACR.
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors: Mir A
authors: MA
authors: Hoda
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Christine
authors: C
authors: Pirker
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors: Yawen
authors: Y
authors: Dong
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors: Karin
authors: K
authors: Schelch
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Petra
authors: P
authors: Heffeter
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Kushtrim
authors: K
authors: Kryeziu
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Sushilla
authors: S
authors: van Schoonhoven
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors: Thomas
authors: T
authors: Klikovits
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors: Viktoria
authors: V
authors: Laszlo
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria. National Koranyi Institute of Pulmonology, Budapest, Hungary.
authors: Anita
authors: A
authors: Rozsas
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors: Judit
authors: J
authors: Ozsvar
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors: Walter
authors: W
authors: Klepetko
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria. National Koranyi Institute of Pulmonology, Budapest, Hungary. Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary. Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.
authors: Balazs
authors: B
authors: Döme
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Michael
authors: M
authors: Grusch
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria. MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
authors: Balazs
authors: B
authors: Hegedüs
authors: Applied and Experimental Oncology, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. walter.berger@meduniwien.ac.at.
authors: Walter
authors: W
authors: Berger
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D018874:Spheroids, Cellular; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D019253:Proto-Oncogene Proteins c-bcl-2; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D002945:Cisplatin