However, delivering these small RNAs to solid tumors remains a significant challenge, as the RNAs must target the correct cells and avoid being broken down by enzymes in the body. To date, most work in this area has focused on delivery to the liver, where targeting is relatively straightforward.
This week in the journal Proceedings of the
Delivering combination therapies
Using the "KP" mouse model, in which a mutant form of the oncogene KRAS is activated and tumor-suppressor gene p53 is deleted, researchers injected mice with RNA-carrying nanoparticles. This mouse model reflects many of the hallmarks of human lung cancer and is often used in preclinical trials. It was originally developed in the laboratory of
The nanoparticles are made of a small polymer lipid conjugate; unlike liver-targeting nanoparticles, these preferentially target the lung, and are well-tolerated in the body. They were developed in the laboratories of co-senior author
In this study, researchers tested the nanoparticle-delivery system with different payloads of therapeutic RNA. They found that delivery of miR-34a, a p53-regulated miRNA, slowed tumor growth, as did delivery of siKRAS, a KRAS-targeting siRNA. Next, researchers treated mice with both miR-34a and siKRAS in the same nanoparticle. Instead of just slowing tumor growth, this combination therapy caused tumors to regress and shrink to about 50 percent of their original size.
Researchers then compared mouse survival time among four treatment options: no treatment; treatment with cisplatin, a small-molecule, standard-care chemotherapy drug; treatment with nanoparticles carrying both miR-34a and siKRAS; and treatment with both cisplatin and the nanoparticles. They found that the nanoparticle treatment extended life just as well as the cisplatin treatment, and furthermore, that the combination therapy of the nanoparticles and cisplatin together extended life by about an additional 25 percent.
Potential for personalized cancer treatments
This early example of RNA combination therapy demonstrates the potential of developing personalized cancer treatments. With efficient delivery of therapeutic RNA, any individual small RNA or combination of RNAs could be deployed to regulate the genetic mutations underlying a given patient's cancer. Furthermore, these RNA therapies could be combined with more traditional drug therapies for an enhanced effect.
"Small-RNA therapy holds great promise for cancer," Jacks says. "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."
"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," says
This investigation typifies the
"This study is a terrific example of the potential of new RNA therapies to treat disease that was done in a highly collaborative way between biologists and engineers," Langer says. "It's an example of what makes the
Contributors to this research from Langer's and Anderson's laboratories include postdocs
This research was supported by grant funding from the
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