The study, “Systemically Administered Rnai Molecule Sensitizes Malignant Pleural Mesothelioma Cells To Pemetrexed Therapy,” conducted by Japanese and Arab researchers, found that blocking the thymidylate synthase (TS) protein through systemic administration of an RNA inhibitor molecule significantly increases tumor cell death in response to Alimta (pemetrexed).
Alimta, a key chemotherapy for the management of MPM, is approved in combination with Platinol (cisplatin) as a first-line treatment of MPM. Still, the overall therapeutic outcome of patients treated with these agents remains poor (40 percent).
Studies have shown that high levels of TS reduced sensitivity to Alimta in different types of tumors. In line with those findings, the researchers had previously demonstrated that decreasing TS expression levels increased the effectiveness of Alimta treatment in MPM cells. They also showed that local injection of an RNA molecule that promotes TS degradation could suppress tumor progression both alone and in combination with Alimta. But this treatment would only be a feasible if the malignant cells were confined to one place.
“It is worth noting that MPM cells are not confined in the thoracic cavity but they have the potential to disseminate not only to neighboring tissues/organs such as regional lymph nodes, pericardium, peritoneum, chest wall but much far to reach the brain,” the researchers wrote.
For this reason, the researchers wanted to evaluate the effectiveness of treating MPM with a chemically produced molecule, called TS shRNA, that could be administered systemically (through intravenous injection) instead of locally, and which still might increase cells’ sensitivity to the toxic effects of Alimta.
Their research confirmed that using the TS shRNA in a cell model of MPM — the human MSTO-211H cells — reduced TS expression levels and significantly enhanced sensitivity of these cells to Alimta, and more cancer cells died after treatment with this drug.
Importantly, the team showed that when the systemic administration of TS shRNA was combined with Alimta in mice models of MPM, the combination had a superior anti-tumor activity, compared to either agent used alone. Reduced tumor growth was achieved by induction of higher rates of cancer cell death in response to the treatment.
Researchers also found that the combination therapy exerted a potent anti-tumor efficacy without causing remarkable toxicity (absence of body weight loss in the animals), and allowed for lower doses of Alimta to be used.
“Systemic treatment strategy is one of the effective therapeutic approaches strategies to treat both primary tumor and metastatic lesions,” the researchers concluded. “These results imply that our tumor targeted anti-TS RNAi system could augment the therapeutic potential of [Alimta] in many clinical settings.”