Small RNA molecules, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), have the potential to serve as therapeutic agents specifically directed to inhibit tumor growth. Nonetheless, the delivering systems used to carry such molecules towards tumor cells are still severely impaired, since they need to correctly target the appropriate cells while avoiding enzyme degradation by the host.
In an attempt to solve this problem, researchers from the Koch Institute for Integrative Cancer Research at MIT have published a study entitled “Small RNA combination therapy for lung cancer” in the Proceedings of the National Academy of Sciences journal, whereby they successfully delivered small RNA therapies in a mouse model of lung cancer.
RNA-carrying nanoparticles composed of a small polymer lipid conjugate and targeting the lung were injected into genetically modified mice that presented an activation of the oncogene KRAS and a deletion of the tumor-suppressor gene p53.
This delivery system was tested with different small RNA particles, however, delivery of miR-34a, a p53-regulated miRNA, and siKRAS, a KRAS-targeting siRNA, significantly delayed tumor growth. Additionally, if both these RNAs were delivered in the same nanoparticle, tumors started to regress and shrink to about half of their original size.
Mouse survival was compared between four different treatment options, including no treatment, treatment with cisplatin (a standard chemotherapy drug), treatment with nanoparticles carrying both miR-34a and siKRAS, and combined treatment with cisplatin and nanoparticles.
The results indicated that nanoparticle-mediated small RNA delivery together with cisplatin-based chemotherapy prolonged survival in this mouse model when compared with chemotherapy alone.
“Small-RNA therapy holds great promise for cancer. It is widely appreciated that the major hurdle in this field is efficient delivery to solid tumors outside of the liver, and this work goes a long way in showing that this is achievable,” said Dr. Tyler Jacks, Koch Institute Director, in an MIT press release.
The data obtained from this research reveals the potential of efficient RNA delivery as a personalized therapeutic strategy able to regulate genetic mutations present in cancer cells. Furthermore, these innovative RNA therapies can be combined with traditional drug therapies for improved results.
“RNA therapies are very flexible and have a lot of potential, because you can design them to treat any type of disease by modifying gene expression very specifically. We took the best mouse model for lung cancer we could find, we found the best nanoparticle we could use, and for one of the first times, we demonstrate targeted RNA combination therapy in a clinically relevant model of lung cancer.” James Dahlman, a graduate student and co-first author of the paper, also said in the press release.
This study was funded by the National Institutes of Health and the National Cancer Institute.