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March 29, 2005 • Volume 2 / Number 13 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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RNAi and Cancer: Silencing Essential Genes


Administrative Supplements Available

Applications are being accepted for administrative supplements for NCI-funded cancer control intervention research R01, P01, P50, U01, and U19 grants. They are designed to provide 1-year funding to cancer control investigators whose intervention efficacy data have been analyzed and who are conducting peer-reviewed research with an active NCI grant award related to the intervention program proposed for dissemination.

Application receipt date is May 30, 2005. For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2647. Inquiries: Dr. Jon F. Kerner- jon.kerner@nih.gov.

The discovery that genes can be silenced by injecting short strands of RNA into cells - a process known as RNA interference or RNAi - has revolutionized biological research. Experiments that once took months or years are now done in days or weeks.

Most laboratories and drug companies working on cancer today use RNAi to identify cancer genes and to investigate the underlying biology of the disease.

"Cancer biologists are using RNAi to do everything from investigating individual genes to running high-throughput screens for new drugs to developing therapeutics," says Dr. Natasha Caplen, head of the Gene Silencing Section in NCI's CCR.

Her group is investigating the mechanics of RNAi in mammalian cells and studying 400 genes associated with cancer, among other projects. "We want to know how we can use this technology to better understand the biology of cancer and the differences between healthy cells and cancer cells," explains Dr. Caplen.

RNAi exploits a defense mechanism in cells that recognizes and degrades the RNA of invaders such as viruses. To turn this mechanism against a cell's own genes, researchers introduce into cells short strands of RNA that correspond to the segments of genes being silenced.

The potential of RNAi to target specific genes was illustrated by a 2002 study, now considered a classic. Dutch researchers silenced mutant RAS genes in human cells leaving normal versions of the gene unaffected.

From a therapeutic perspective, the prospect of being able to turn off specific genes in tumor cells has long intrigued cancer researchers. But the science is still in its infancy, and RNAi can cause "off-target" effects. A major challenge is finding ways to get the RNA where it needs to go for a sufficient amount of time to benefit patients.

"The big issue with RNAi is delivery," says Dr. John J. Rossi of the Beckman Research Institute in Duarte, California. "We know we can get RNAi to work, but for the most part the delivery is not very specific and not very efficient."

Last year, biologists at Alnylam Pharmaceuticals in Germany addressed the delivery problem and showed that RNAi could be used to lower cholesterol levels in mice.

The team attached RNA molecules to cholesterol and injected them into the rodents' bloodstreams. The composite molecules were taken up by the liver, where blocking a gene helped lower blood cholesterol levels, according to findings in the Nov. 11, 2004, issue of Nature.

"The mouse study proved that delivery will be solvable for RNAi," says Dr. Judy Lieberman of Harvard Medical School in Boston, who co-authored an article in the March 16 Journal of the American Medical Association about using RNAi to treat disease. "They delivered the therapy to specific cells and saw a clinical effect."

Dr. Lieberman says that reliable cell-specific delivery would be "incredibly powerful" for cancer because researchers could target not only cancer genes but also other genes necessary for cell growth or cell division. "You might target four genes simultaneously and really restrict a cancer cell's ability to survive," she says.

While RNAi may not treat cancer for many years, if ever, the science is moving forward at a fast pace. Several groups are building large collections of RNA molecules that can be used to explore all manner of biological questions.

RNAi is increasingly being used, for instance, to investigate the mechanisms of action of drugs. Some medications work for unknown reasons, and RNAi can be used to identify the genes involved.

In fact, the technology can be used to identify the genes required for just about anything that happens in cells, according to Dr. Louis Staudt of NCI's CCR.

His team developed an RNAi-based method to identify the genes that cancer cells need to survive and proliferate. In this method, retroviruses are used to express about 2,000 different RNAi's in cancer cells, and then DNA microarrays are used to determine which of the RNAi's target essential genes regulate cancer cell growth and survival.

"It's an exciting time when you can look across thousands of genes simultaneously and probe their functions in human cancer," says Dr. Staudt.

High-throughput screening is another way to identify essential genes in cancer and potential drug targets. For example, the Translational Genomics Research Center (TGen) in Maryland has a large collection of RNA molecules and exposes the molecules to cancer cells in parallel, thousands at a time.

"We are using RNAi to discover new points of vulnerability in cancer cells," says Dr. Spyro Mousses of TGen. Another project is to use RNAi to identify genes that, when silenced, make cancer cells more sensitive to chemotherapy.

Though not in the area of cancer, two clinical trials are testing RNAi as therapy for age-related macular degeneration. The delivery method is injection into the eye, and the findings will likely add to the growing knowledge about the fast-moving science of gene silencing.

By Edward R. Winstead