Nanoparticles Shut Off Cancer Genes - A New Tool for Screening Drug Targets
By sequencing cancer-cell genomes, scientists have discovered vast numbers of genes that are mutated, deleted or copied in cancer cells. This treasure trove is a boon for researchers seeking new drug targets, but it is nearly impossible to test them all in a timely fashion. To help speed up the process, researchers in the MIT-Harvard Center of Cancer Nanotechnology Excellence (MIT CCNE) have developed RNA-delivering nanoparticles that allow for rapid screening of new drug targets in mice. In their first mouse study, done with researchers at Dana-Farber Cancer Institute and the Broad Institute, they showed that nanoparticles that target a protein known as ID4 can shrink ovarian tumors.
The nanoparticle system, developed by Sangeeta Bhatia and her colleagues, is described in journal Science Translational Medicine. “What we did was try to set forth a pipeline where you start with all of the targets that are pouring out of genomics, and you sequentially filter them through a mouse model to figure out which ones are important. By doing that, you can prioritize the ones you want to target clinically using RNA interference, or develop drugs against,” says Dr. Bhatia.
The MIT CCNE team collaborated with William Hahn, of Harvard Medical School, who is the leader of Project Achilles, a collaborative effort to identify promising new targets for cancer drugs from the flood of data coming from the National Cancer Institute’s cancer-genome-sequencing project. Among those potential targets are many considered to be “undruggable,” meaning that the proteins do not possess enzyme activity to which inhibitors can be developed. The new nanoparticles, which deliver short strands of RNA that can be designed to shut off any particular gene, may help scientists go after those undruggable proteins.
Through Project Achilles, Dr. Hahn and his colleagues have been testing the functions of many of the genes disrupted in ovarian cancer cells. By revealing genes critical to cancer-cell survival, this approach has narrowed the list of potential targets to several dozen.
An important step in identifying a good drug target would be to genetically engineer a strain of mice that are missing (or overexpressing) the gene in question, to see how they respond when tumors develop. However, this normally takes two to four years. A much faster way to study these genes would be simply to turn them off after a tumor appears. RNA interference (RNAi) offers a promising way to do that. During this naturally occurring phenomenon, short strands of RNA bind to the messenger RNA (mRNA) that delivers protein-building instructions from the cell’s nucleus to the rest of the cell. Once bound, the mRNA molecules are destroyed and their corresponding proteins never get made.
Scientists have been pursuing RNAi as a cancer treatment since its discovery in the late 1990s, but have had trouble finding a way to safely and effectively target tumors with this therapy. Of particular difficulty was finding a way to get RNA to penetrate tumors. Dr. Bhatia’s lab, which has been working on RNAi delivery for several years, joined forces with Dr. Hahn’s group to identify and test new drug targets. Their goal was to create a “mix and dose” technique that would allow researchers to mix up RNA-delivery particles that target a particular gene, inject them into mice, and see what happens.
In their first effort, the researchers decided to focus on the ID4 protein because it is overexpressed in about a third of high-grade ovarian tumors and because they found it was crucial for ovarian cancer growth. The gene, which codes for a transcription factor, appears to be involved in embryonic development. It gets shut down early in life, then reactivates in ovarian tumors. To target ID4, Dr. Bhatia and her collaborators designed a new type of RNA-delivering nanoparticle, These particles can both target and penetrate tumors, something that had never before been achieved with RNAi. In a study of mice with ovarian tumors, the researchers found that treatment with the RNAi nanoparticles suppressed 80-90% of tumor growth.
The investigators are now using the particles to test other potential targets for ovarian cancer as well as other types of cancer, including pancreatic cancer. They are also looking into the possibility of developing the ID4-targeting particles as a treatment for ovarian cancer.
This work, which is detailed in a paper titled, “Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4,” was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal's website.