Scientists inhibit cancer gene

Potential therapy for up to 30 percent of human tumors

By studying mice with skin cancer, researchers at the Huntsman Cancer Institute at the University of Utah discovered a way to inhibit a mutant gene found in up to 30 percent of human tumors.

Called Ras, normal copies of this gene are important in cell signaling, or communication among cells. When mutated, however, Ras is an “oncogene” or cancer-causing gene that has been shown to promote the growth of cancers in the pancreas, colon and lung, as well as thyroid cancer and leukemia.

Attempts to inhibit activated Ras have had limited success until now, but the Huntsman Cancer Institute researchers explain that they have discovered an enzyme that, when inhibited, appears to reduce the incidence of Ras-induced tumors in mice.

They reported their findings in the May 9 – 13, 2005, issue of the journal Proceedings of the National Academy of Sciences Online Early Edition.

Matthew K. Topham, M.D., assistant professor of internal medicine at the University of Utah School of Medicine and lead investigator on the study, explains that the research team had originally been testing a group of enzymes that regulate the function of the Ras gene. These enzymes, called diacylglycerol kinases (DGKs), are implicated in tumor growth.

“When we began our investigation using a type of DGK, called DGK iota, we thought that its absence would cause more tumors to develop, as has happened with other DGKs we have tested. This time, though, when we tested mice with an activated Ras gene, but an absent DGK iota gene, the number of tumors was significantly reduced,” Topham says. “This result is interesting, because it happened when the Ras gene was activated. The implication is that a drug therapy could be developed to reduce tumors caused by Ras without significant side effects.”

The research team also included Huntsman Cancer Institute scientists Debra Regier, Ph.D.; Jared Higbee; Katrina Lund; Fumio Sakane, Ph.D.; and Stephen M. Prescott, M.D., professor of internal medicine at the University of Utah and executive director of Huntsman Cancer Institute.

The researchers used mice that were bred to have a highly “expressed” — meaning highly active — mutant of the Ras oncogene. Such mice were first developed years ago. Prior studies had demonstrated that these mice were very prone to tumors. For the new study, the Hunstman Cancer Institute team deleted the DGK iota gene in these mice and found that they developed few tumors, while mice with an intact DGK iota gene and an activated Ras gene exhibited significantly more tumors.

Topham says his team will now examine more closely the mechanism behind how DGK iota works to inhibit tumor formation.