Dec 18, 2008

Science - Nobel-Winning Science May Help Combat Deadly Tumors

John Lauerman

Dec. 17 (Bloomberg) -- Nobel Prize-winning science has given cancer researchers a clue why some poorly understood tumors become lethal.

Ovarian tumors, which are difficult to detect and will kill more than 15,000 U.S. women this year, were linked to a genetic process that was found in humans in the last two decades and won its discoverers science’s highest award two years ago. Scientists reported the connection to the tumors today in the New England Journal of Medicine.

Tumors of the ovary were more dangerous when they lacked enzymes needed for RNA interference, a process of genetic control that has been found to affect cell growth as well as cancer. Measurements of the enzymes may help doctors determine which cancer patients are at highest risk, and restoring levels of these proteins may help treatment, said Anil Sood, a researcher for the M.D. Anderson Cancer Center, at the University of Texas in Houston.

Most ovarian cancer patients are diagnosed “in the advanced stages of the disease, and that’s part of the reason why they have such poor overall survival,” he said yesterday in a telephone interview. “This work may have many, many implications for the diagnostics and prognostics of cancer.”

Since the complete human genetic code was deciphered in 2003, researchers have been finding that its instructions to cells are far more complicated than imagined. One recent discovery is that organisms depend on RNA, a mirror-image molecule to DNA, to regulate numerous cellular functions. Laboratories around the world now use RNA interference to study the roles of individual genes and proteins in cells,

One group of RNA interference molecules under study is called microRNAs. These molecules appear to control groups of genes, and abnormalities in them have been linked to breast and prostate cancers.

Dicer, Drosha

Sood, a women’s cancer specialist who has been studying RNA interference for about six years, looked at levels of enzymes called Dicer and Drosha in ovarian cancer cells. The two enzymes process microRNAs, shaving them to the right lengths to perform their functions.

Dicer levels were about 60 percent lower than normal in ovarian cancers, and Drosha levels were about half their usual level. Cells with the lowest enzyme levels were most likely to have progressed to the most dangerous and difficult-to-treat stages, the study found.

Sood’s group got similar results when they examined earlier studies that looked at Dicer expression in lung and breast cancer. The information helps answer questions raised by earlier studies as to whether microRNAs promote cancer or suppress it, Sood said. The deficit in cancer cells suggests they normally play a protective role, he said.

“Our findings would suggest that some microRNAs would have suppressive functions,” he said.

Alnylam, Novartis, Roche

Alnylam Pharmaceuticals Inc., Novartis AG, and Roche Holding AG are among companies investigating treatments based on the technology. One goal is to use another set of molecules, called small interfering RNAs, or siRNAs, to block or control specific genes that may contribute to disease.

Using colonies of cancer cells, the scientists showed that even in the presence of low Dicer and Drosha levels, siRNA molecules continued to have their effect, temporarily blocking gene activity. That removes a potential roadblock to the use of siRNAs as cancer drugs, said John Maraganore, Alnylam’s chief executive officer.

‘Good Piece of News’

“That’s a good piece of news for us and we hadn’t expected it until we saw this paper,” he said. The company is preparing to file for permission from the Food and Drug Administration to begin work on a new liver cancer drug, he said in a phone interview.

Alnylam rose 32 cents, or 1.4 percent, to $23.29 at 4 p.m. New York time in Nasdaq Stock Market composite trading. The company has dropped 20 percent this year.

Researchers who want to use microRNAs in cancer treatment will have to find ways to do it in cells with low levels of the critical enzymes, said Frank Slack, a Yale University associate professor of molecular, cellular and developmental biology, who wrote a companion editorial in the same journal.

“We need to think about using microRNAs in ways that don’t require Dicer and Drosha processing,” he said in a telephone interview. “There’s no sense in giving the upstream product if they can’t be processed into the active molecule.”

To contact the reporter on this story: John Lauerman in Boston at

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