Turning Off Tumors

New RNA-­delivering nanoparticles developed at MIT could give scientists a much faster way to identify potential genetic targets for new cancer drugs. In a study done with researchers at Dana-­Farber Cancer Institute and the Broad Institute, the MIT team used the technique to show that targeting a protein known as ID4 can shrink—or even eliminate—ovarian tumors in mice.

The nanoparticle system could relieve a significant bottleneck in cancer drug development, says ­Sangeeta Bhatia, a professor of health sciences and technology and of electrical engineering and computer science, who is also a member of the David H. Koch Institute for Integrative Cancer Research at MIT. Typically, when a gene thought to be associated with cancer cells’ survival is identified, researchers genetically engineer a strain of mice in which the target gene is missing or overactive, to see how the cells respond when tumors develop. However, this process normally takes two to four years. A much faster way to study these genes would be to simply turn them off after a tumor appears. RNA interference (RNAi), which prevents delivery of protein-building instructions from the cell’s nucleus to the rest of the cell, offers a promising way to do that.

For this study, Bhatia’s lab joined forces with William Hahn, an associate professor of medicine at Harvard Medical School and the leader of Project Achilles, which seeks to identify promising new targets for cancer drugs in the flood of data coming from the National Cancer Institute’s effort to sequence cancer genomes. Their goal was to create a “mix and dose” technique that would allow researchers to take a type of RNA that targets a particular gene and mix it with the other components of delivery particles, inject the resulting particles into mice with tumors, and see what happened.

Bhatia and her students designed a new type of nanoparticle that delivers short strands of RNA to a cell. Those strands interfere with the cell’s existing messenger RNA, shutting off a target gene as the tumors grow. The particles can both target and penetrate tumors, something that had never before been achieved with RNA interference.

The researchers decided to target the ID4 protein because it is overproduced in about a third of high-grade ovarian tumors (the most aggressive kind), but not in other cancer types. The gene appears to be involved in embryonic development; it gets shut down early in life and then somehow reactivates in ovarian tumors. In a study of mice with ovarian cancer, the researchers found that treatment with the RNAi nanoparticles shrank or eliminated all the tumors.

Bhatia and her group are now testing other potential targets for ovarian cancer as well as other forms of the disease, including pancreatic cancer. They are also looking into the possibility of developing ID4-silencing particles as a treatment for ovarian cancer.