Yondelis (trabectedin), an anti-tumor drug approved for the treatment of advanced soft tissue sarcoma and ovarian cancer, has shown promising results in malignant pleural mesothelioma (MPM) cells, exerting strong anti-tumor activity.
The study, “Trabectedin is active against malignant pleural mesothelioma cell and xenograft models and synergizes with chemotherapy and bcl-2 inhibition in vitro,” published in Molecular Cancer Therapeutics, shows that Yondelis’ effectiveness increases when it is combined with the chemotherapy drug Platinol (cisplatin) or with other drugs that induce cell death.
Patients with MPM have low median survival rates in part due to the resistance against systemic therapeutic options. Currently, the preferred treatment options include chemotherapy with Alimta (premetrexed) or Platinol, or aggressive cytoreductive therapy combined with chemotherapy and radiation therapy, which prolongs survival in selected MPM patients. However, due to the limited treatment options in more advanced stages of MPM, a better understanding of the disease is required to identify new targets for therapy.
Recently, the anti-cancer potential of marine-based cytotoxic compounds has been receiving increasing attention. Yondelis, which is originally isolated from the Caribbean marine tunicate Ecteinascidia turbinate, has been shown to exert potent anti-tumor activity against human tumors, including melanoma, non-small cell lung cancer, and ovarian cancer.
The drug works through two distinct mechanisms. First, it binds to the DNA and prevents DNA-repair mechanisms, blocks the expression of several tumor-promoting genes (oncogenes) and factors that induce drug resistance. Then, it interacts with cells from the tumor microenvironment, particularly macrophages, preventing their pro-tumoral activity.
Researchers wanted to explore the role of Yondelis in MPM cell lines and in mice bearing human MPM tumors. They found that the drug exerted a dose-dependent cytotoxic effect — disturbing the cell cycle and inducing cell death — both on MPM cell lines and primary cells isolated from MPM patients, but the non-malignant mesothelial cells were significantly less responsive to the drug.
Importantly, the researchers found that combining Yondelis with Platinol or Obatoclax, a bcl-2 inhibitor that induces cell death, markedly increased its anti-tumor effects.
Furthermore, the team, led by Walter Berger also showed that Yondelis exerted significant activity against intraperitoneal MPM mice models, reducing tumor growth without major toxicity to the animals.
These results show that Yondelis is active as a single agent against human MPM cells both in vitro and in vivo by directly targeting anti-cell death mechanisms. However, its effect can be enhanced by chemotherapeutic agents or agents inducing cell death. Together this suggests that combination approaches with Yondelis may be promising therapeutic options for MPM patients.