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 which 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 non-malignant pleural tissues samples (N=2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or non-adherent spheroids with IC50 values {less than or equal to} 2.6 nM. Non-malignant mesothelial cells were significantly less responsive. The strong anti-mesothelioma activity was based on cell cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by co-administration 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. Additionally, 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.