Researchers at the University Hospitals Ireland Cancer Center and the Case Comprehensive Cancer Center have made a significant discovery that may lead to a new drug to prevent colon cancer. Sanford Markowitz, M.D., Ph.D., a Howard Hughes Medical Institute investigator, and a research team have published their findings on a ’Celebrex-like’ gene that suppresses the growth of colon cancer this week in the Proceedings of the National Academy of Sciences.

The researchers confirmed that the gene, called 15-PGDH, is found in normal cells and is virtually undetectable in colon cancer cells. When the researchers restored the gene in tumor cells and injected them into immune-deficient mice, the mice showed little or no tumor development. The research is based on a study published in PNAS in December 2004. The gene 15-PGDH acts as an antagonist to control an enzyme called COX-2. An increase in COX-2 is a major early event in the genesis of human colon tumors. 

"This discovery will spur us on to try to develop a drug for boosting PGDH levels and thereby help to prevent the development of colon cancer," says Dr. Markowitz, the Francis Wragg Ingalls Professor of Cancer Genetics at Case Western Reserve University and UH and senior author of the paper. "In colon cancers a dramatic increase of COX-2 is seen. 15-PGDH would act to antagonize and check this increased COX-2 activity. Without 15-PGDH present, unchecked COX-2 goes on to cause abnormal changes on the cellular level, which may lead to tumor development."

Previous studies have shown that patients who take nonsteroidal anti-inflammatory drugs (NSAIDs), which are COX-2 inhibitors, have a lower incidence of colon cancer. COX-2 inhibitors have been shown to shrink the size of tumors in mice. Markowitz likens the 15-PGDH gene to a naturally occurring COX-2 inhibitor. (Celebrex, a popular arthritis drug, is also a COX-2 inhibitor.)

Markowitz and his team found that 15-PGDH is directly controlled and activated by another gene, called TGF-beta. Normally, TGF-beta sends a signal that allows the colon to shed cells weekly as a way of helping to block development of colon cancers. In 1995, Markowitz discovered colon cancers have mutations that inactivate the TGF-beta pathway. "If there is no TGF-beta signal, there is no 15-PGDH. That means the opponent to COX-2 is gone, and the COX-2 oncogene activity is unopposed," said Markowitz.

"This interaction between TGF-beta and 15-PGDH points to the importance of the TGF-beta system in suppressing colon cancer. These genes give us targets that we can aim for in the development of new drugs or gene therapies that may help us treat or prevent colon cancer," said Markowitz, who is also an investigator with the Howard Hughes Medical Institute.

Lead authors on the paper are Min Yan of the departments of medicine, molecular and microbiology at Case Western Reserve University School of Medicine and the Ireland Cancer Center at University Hospitals, and Ronald M. Rerko of Howard Hughes Medical Institute. Also involved were researchers from the University of Kentucky and the Protein Design Laboratories in Freemont, Calif.