Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro

Our plain-English summary of Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro, by M.A. Hoda, C. Pirker, Y. Dong, et al (Molecular Cancer Therapeutics, 2016).

The study

• Authors: M.A. Hoda, C. Pirker, Y. Dong, K. Schelch, P. Heffeter, K. Kryeziu, S. van Schoonhoven, T. Klikovits, V. Laszlo, A. Rozsas, J. Ozsvar, W. Klepetko, B. Döme, M. Grusch, B. Hegedüs, W. Berger
• Journal: Molecular Cancer Therapeutics
• Published: 2016;15(10):2357-2369
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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 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.

©2016 American Association for Cancer Research.

In plain English

This was a laboratory study of a cancer drug. It did not study patients or asbestos exposure. The authors tested trabectedin on malignant pleural mesothelioma cells: six cell lines, 13 primary cultures from surgical specimens, and two cultures from non-malignant pleural tissue. They also tested it on human mesothelioma cells grown in the abdomen of 10 mice. Trabectedin reduced the viability of all the mesothelioma cell models, with IC50 values at or below 2.6 nM. The IC50 is the drug concentration that cuts cell viability by half. The non-malignant cells were less sensitive, with a mean IC50 of 3.39 nM. The drug triggered programmed cell death (apoptosis) and disrupted cell division. In the mice, a single injection lowered mean tumor weight by 43% (542 mg in treated mice versus 943 mg in mice given salt solution). In cell experiments, trabectedin acted synergistically with cisplatin and with the bcl-2 inhibitor obatoclax. With pemetrexed the effects were mainly additive to antagonistic. The authors concluded that their data suggest developing trabectedin, especially in drug combinations. They noted that a trabectedin-cisplatin experiment in mice was stopped early because of toxicity, and that the bcl-2 combination still needs testing in animals.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: preclinical laboratory study: cell culture experiments plus a mouse xenograft experiment
• Who was studied: 6 malignant pleural mesothelioma (MPM) cell lines, 13 primary MPM cell cultures from surgical specimens, and 2 cultures from non-malignant pleural tissue (from pneumothorax operations); plus 10 female SCID mice (5 per group) injected intraperitoneally with SPC111 mesothelioma cells
• Exposure: the drug trabectedin alone (in cells at nanomolar and picomolar concentrations; in mice a single intravenous dose of 0.15 mg/kg) and combined with cisplatin, pemetrexed, and the bcl-2 inhibitors obatoclax and ABT-199; no asbestos exposure was studied
• Main results:
  • In all malignant cell models, trabectedin reduced viability with IC50 values at or below 2.6 nM, often in the picomolar range
  • Non-malignant mesothelial cell cultures were less sensitive, with a mean IC50 of 3.39 nM
  • In MPM cell lines, 0.1 nM trabectedin suppressed colony formation by more than 50%
  • Spheroid (3D cell cluster) formation was completely blocked at 5 nM in both biphasic and epithelioid cell lines
  • Apoptosis rates were significantly increased at 1 nM trabectedin in all four cell lines tested
  • Cell invasion was weakly but significantly inhibited at 0.5 and 1 nM in three of four MPM cell lines; cell migration was not significantly inhibited up to 1 nM, except in SPC111 at 8 and 12 hours
  • Trabectedin caused cells to accumulate in the G2 phase of the cell cycle
  • In mice with intraperitoneal SPC111 tumors, a single trabectedin injection reduced mean tumor weight by 43%: 943 plus or minus 45 mg in the solvent group versus 542 plus or minus 15 mg in the trabectedin group (p less than 0.0001)
  • In cell experiments, cisplatin combined with trabectedin had mainly synergistic effects; pemetrexed had mainly additive to antagonistic effects
  • The bcl-2 gene showed the strongest expression difference between less and more trabectedin-responsive cell models, at 4.4-fold higher in the low-responsive subgroup
  • Trabectedin with obatoclax showed synergism (combination index below 0.9) in all cell models tested; with ABT-199 the effects were mostly additive to synergistic
• The authors' conclusion: The authors concluded that trabectedin is active as a single agent against human MPM in vitro and in vivo, and that their data suggest developing trabectedin especially in combination approaches
• Limitations the authors state:
  • An attempt to combine trabectedin and cisplatin in mice was stopped early because of local toxicity at injection sites and weight loss
  • The synergy between trabectedin and bcl-2 inhibitors was shown only in cell culture and still needs confirmation in animal models

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Systemic Therapy, Tumor Microenvironment, Sarcoma, Ovarian Cancer, Mesothelial Cells, Apoptosis.

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