Dual-drug therapy targets one colon cancer gene

Johns Hopkins Kimmel Cancer Center scientists have found that interferon, used for 30 years to treat blood cancers, multiple sclerosis and hepatitis, selectively kills colon cancer cells when combined with another standard chemotherapy agent. New studies in cell lines suggest that the combination tactic, which targets a common gene pathway in colon cancer cells, could be more potent than either drug alone, and has fewer side effects.

“Instead of killing a tree by chopping it down, this approach focuses on cutting off the diseased branch, leaving the rest of the tree relatively unscathed,” says Betsy Barnes, Ph.D., assistant professor of oncology and lead researcher.

By itself, interferon’s cell-killing activity is non-specific in targeting a variety of cells and cell-based gene activity, causing serious side effects such as heart failure and low blood counts, in addition to killing cancer cells. But in an August 15 issue of Cancer Research, the Kimmel Cancer Center scientists found one factor in interferon’s makeup that could have cancer-killing qualities, but with fewer side effects since it activates fewer genes.

Specifically, the team found that IRF5 (Interferon Regulatory Factor-5), which works as a tumor suppressor to halt cancer cell growth, is turned off by many cancers, but low levels of the suppressor protein are found in most colon cancers. That led Hopkins’ Barnes and her team to pursue its potential.

The first thing they found is that although interferon boosts IRF5 protein levels in colon cancer cells, it does not raise it enough to kill the cells. To boost IRF5 levels, the investigators combined interferon with a chemotherapy drug called irinotecan (CPT-11), a drug that damages DNA in rapidly dividing cells, rendering them unable to divide.

“We believe that interferon and irinotecan both work to increase IRF5 protein levels, but irinotecan activates the protein in the final step to initiate cancer cell death,” says Barnes.

To demonstrate their theory that IRF5 is a key ingredient in the dual-drug therapy, the scientists tested various combinations of the drugs in colon cancer cell lines, with or without IRF5. Irinotecan alone causes 65 percent cell death in lines with IRF5 proteins present. Knock out IRF5 proteins and cell deaths drop to 37 percent. When the investigators combined irinotecan and interferon, more than 80 percent of colon cancer cells with IRF5 proteins died. Only 28 percent of cells died in those lines with IRF5 proteins knocked out.

“Not only does the combination of these drugs involve fewer gene activations, it may allow use of smaller amounts of both drugs and limit side effects,” says Barnes. She also believes that cancer cells may find it more difficult to build resistance to two different drugs, a common problem when using single agents.

Cancers lacking tumor suppressor genes and the proteins they make are often difficult to treat because cells are unable to put the brake on abnormal growth. Her study indicates that IRF5 applies the brakes even in the absence of other tumor suppressor genes.

It is not clear whether the combination therapy would work in other cancers, since IRF5 is absent in a number of blood cancers. But since colon cancer is the third deadliest cancer in the United States, Barnes and her team will conduct further tests in genetically modified mice and potentially create a new strategy to treat the disease.

Colon cancer strikes more than 100,000 people in the United States annually and kills more than 56,000.

Funding for this research was provided by the American Cancer Society and a Flight Attendant Medical Research Institute Young Clinical Scientist Award.

Barnes’ research team on this study included Guodong Hu and Margo E. Mancl from Johns Hopkins.