Researchers in Japan have taken another important step toward creating a novel therapeutic strategy for malignant pleural mesothelioma, a highly treatment-resistant and deadly form of lung cancer.
Following up on research they conducted earlier this year, doctors at Tokushima University’s Institute of Health Biosciences successfully boosted the effectiveness of chemotherapy and prolonged mesothelioma survival in mice by manipulating their RNA.
RNA and Malignant Mesothelioma
Ribonucleic acid (RNA) is a molecule that acts as a messenger, carrying and translating instructions from DNA that control critical cellular processes, from metabolism to replication and cell death (apoptosis).
Cancer researchers have found that, by “reprogramming” the RNA using specially designed molecules, they can enhance the effectiveness of certain chemotherapy agents, including pemetrexed (Alimta), the only drug specifically approved to treat malignant mesothelioma. This type of manipulation is known as RNAi or “RNA interference”.
In their earlier study, the research team used RNAi at the mesothelioma tumor site to successfully downregulate an enzyme called thymidylate synthase (TS) which helps protect mesothelioma cells from the damaging effects of chemotherapy.
In the newest study, they used the same method systemically, administering the altered RNA along with pemetrexed throughout the bodies of mesothelioma-infected mice.
Enhancing Chemotherapy for Mesothelioma
To deliver the new “programming” into the nuclei of mesothelioma tumor cells, the researchers first embedded the newly-created RNA molecule in a bubble of fat and coated it with polyethylene glycol (PEG). The resulting “lipoplex” was injected after pemetrexed infusion into mice with mesothelioma.
“The combined treatment of pemetrexed with systemic injection of PEG-coated TS shRNA-lipoplex exerted potent antitumor activity against MSTO-211H [a mesothelioma cell line] xenograft mouse model, compared to a single treatment with either pemetrexed or PEG-coated TS shRNA-lipoplex,” writes lead author Dr. Amr Abu Lila.
Dr. Abu Lila and his team speculate that combining this kind of systemic (throughout the body) RNAi with the same treatment at the tumor site might be an option to “extend the clinical utility of pemetrexed in treating malignant mesothelioma”.
Even though pemetrexed is approved to treat malignant mesothelioma, it is only marginally effective for most patients. Most mesothelioma patients have to undergo several different kinds of treatment, including surgery and/or radiation, in addition to chemotherapy, to try to stop the spread of their tumors.
If it can be confirmed that RNAi makes mesothelioma cells more susceptible to pemetrexed treatment, it could dramatically improve the odds of survival for thousands of mesothelioma patients.
The new study appears in a recent issue of Molecular Pharmaceutics.
Abu Lila, AS, et al, “Systemically administered RNAi molecule sensitizes malignant pleural mesothelioma cells to pemetrexed therapy”, October 14, 2016, Epub ahead of print