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Ref Type Journal Article
PMID (27512118)
Authors Hoda MA, Pirker C, Dong Y, Schelch K, Heffeter P, Kryeziu K, van Schoonhoven S, Klikovits T, Laszlo V, Rozsas A, Ozsvar J, Klepetko W, Döme B, Grusch M, Hegedüs B, Berger W
Title Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro.
Journal Molecular cancer therapeutics
Vol 15
Issue 10
Date 2016 Oct
URL
Abstract Text 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 IC50 values ≤ 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-xL as 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown malignant pleural mesothelioma not applicable Trabectedin Preclinical - Cell line xenograft Actionable In a preclinical study, Yondelis (trabectedin) inhibited growth and increased apoptosis of malignant pleural mesothelioma (MPM) cell lines in culture, decreased viability of primary MPM cells in culture, and inhibited tumor growth in MPM cell line xenograft models (PMID: 27512118). 27512118
Unknown unknown malignant pleural mesothelioma not applicable Trabectedin + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, the combination of Yondelis (trabectedin) and Venclexta (venetoclax) demonstrated synergistic or additive effects on decreasing viability of malignant pleural mesothelioma cell lines in culture (PMID: 27512118). 27512118
Unknown unknown malignant pleural mesothelioma not applicable Obatoclax + Trabectedin Preclinical - Cell culture Actionable In a preclinical study, the combination of Yondelis (trabectedin) and Obatoclax (GX015-070) demonstrated synergy in inducing apoptosis and decreasing viability of malignant pleural mesothelioma cell lines in culture (PMID: 27512118). 27512118
Unknown unknown malignant pleural mesothelioma not applicable Cisplatin + Trabectedin Preclinical - Cell culture Actionable In a preclinical study, the combination of Yondelis (trabectedin) and Platinol (cisplatin) demonstrated synergy in inducing apoptosis and decreasing viability of malignant pleural mesothelioma cell lines in culture (PMID: 27512118). 27512118