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Mouse-to-Mouse Revelation: Genome Yields Cancer Drug Target
  
By Nancy Touchette

The completion of the human genome sequence has been accompanied by promises of great advances in health care and medicine, but when the public might begin to reap these benefits has been an open question. Now, a new study suggests that the genome may live up to its potential sooner than some had thought.

Researchers looking to develop new cancer therapies have turned up an unlikely target: a gene previously linked to Down syndrome. They found that a shortened form of the gene, called Single Minded 2 (SIM2), was overly active in colon, prostate, and pancreatic tumors but not in other cancers or normal tissues.

Ramaswamy Narayanan and his colleagues at Florida Atlantic University in Boca Raton scoured the genome for genes that were active, or expressed, in cancer tissues. Based on the DNA sequence, the researchers designed an inhibitor of the gene, which blocked the growth of human colon tumors in mice.

“This is a ‘mouse-to-mouse’ prediction of a new cancer target,” says Narayanan. “With the computer mouse, we were able to find genes active in tumors, but not normal tissues. Using that information, we developed a drug that inhibits tumors in the mouse.”

The researchers made use of the Cancer Genome Anatomy Project (CGAP), a database maintained by the National Cancer Institute in Bethesda, Maryland. The database includes genomic information such as the sites of chromosomal ‘breakpoints,’ which are associated with some diseases, and the DNA sequences of genes active in cancer tissues.

“This is a classic example of how the cancer genome data are intended to be used,” says Robert Stausberg, director of NCI’s Cancer Genomics Program. “They found a gene that is over-expressed in some tumors and said, ‘Gee this gene might be useful as a target for intervention.’”

The single minded gene was originally discovered in the fruit fly Drosophila, where it plays a role in the development of the nervous system. Humans have at least two genes similar to single minded in flies: SIM1, located on chromosome 6, is thought to contribute to obesity when mutated; SIM2 is thought to play a role in the facial abnormalities that occur in many Down syndrome patients.

Researchers were initially surprised to implicate SIM2 in cancer. Although Down syndrome patients have a higher risk of developing leukemia, they do not have a higher incidence of any solid tumors.

Narayanan found that a truncated form of the SIM2 gene is produced in certain cancers instead of the normal, long form of the gene. He speculates that the short form contributes to tumor development by displacing the long form, which can regulate the production of enzymes that inactivate carcinogens.

The researchers synthesized a molecule, called antisense DNA, to block the activity of the SIM2 gene. When they treated mice with tumors derived from human colon cancer cells, they observed significant reduction in tumor growth and an increase in the programmed death of tumor cells.

Narayanan has started a new biotech company to move his discovery from the laboratory to the clinic. The company is developing a diagnostic test for colon and prostate cancer based on the SIM2 gene. They also hope to test the SIM2 inhibitor in clinical trials as a potential therapy for pancreatic cancer, for which there are few treatments.

If Narayanan succeeds, this will not be the first new cancer drug based on a known gene. Gleevec, which is used to treat acute myelogenous leukemia (AML), was developed after researchers found that chromosome breakage and fusion in AML resulted in the fusion of two cancer genes. And Herceptin, which is used to treat breast cancer, evolved from studies showing an elevated activation of the HER2 gene in certain aggressive breast tumors.

However, Narayanan’s study is one of the first to discover a new cancer-associated gene solely from genome sequence data.

“The study provides a rational basis for discovering new cancer targets based on the sequence of the human genome,” says Tej Panditat of a cancer biologist at Washington University in St. Louis, Missouri. “Two different diseases have been linked through the same gene.”

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DeYoung, M.P. et al. Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors. Proc Natl Acad Sci USA 100, 4760-4765 (April 15, 2003).
 

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