A study involving CALS researchers has linked two seemingly unrelated cancer treatments that are both being tested in clinical trials. One treatment is a vaccine that targets a structure on the outside of cancer cells. The other is a slightly altered human enzyme that breaks apart RNA and causes the cell to self-destruct.
The new understanding could help both approaches, says biochemistry professor Ronald Raines, who has long studied ribonucleases—enzymes that break apart RNA, a messenger with multiple roles inside the cell. In 1998, he discovered how to alter one ribonuclease to avoid its deactivation in the body. Soon thereafter, he found that the engineered ribonuclease was more toxic to cancer cells than to others.
Raines patented the advance through the Wisconsin Alumni Research Foundation (WARF) and, with fellow CALS biochemist Laura Kiessling, co-founded Quintessence Biosciences in Madison. They remain shareholders in the firm, which has licensed the patent from WARF and begun early-phase human trials with the ribonuclease at the UW Carbone Cancer Center and MD Anderson Cancer Center in Houston.
The current study began as an effort to figure out why the ribonuclease was selective for cancer cells. To identify which structure on the cell surface helped it enter the cell, Raines screened 264 structures using a specially designed chip. The winner was a carbohydrate called Globo H.
“We were surprised—delighted!—to see that, because we already knew that Globo H is an antigen that is abundant in many tumors,” says Raines. Antigens are molecules with structures that are recognizable to proteins called antibodies. “Globo H is under development as the basis for a vaccine that will teach the immune system to recognize and kill cancer cells,” he says.
Working with Samuel Danishefsky, who solved the difficult problem of synthesizing Globo H at the Memorial Sloan-Kettering Cancer Center in New York, Raines found that reducing the Globo H display on their surface made breast cancer cells less vulnerable to ribonucleases like those that Quintessence is testing. “This was exciting, as we now have a much clearer idea of how our drug candidate is working,” says Raines.
CALS biochemistry professor John Markley aided the research with studies of the structure of the molecules in question.
The picture that emerges from their work is of ribonucleases patrolling our bodies, looking for signs of cancer cells, Raines says: “We are working to demonstrate this surveillance more clearly in mice.”
As other scientists test whether using a vaccine will start an immune attack on Globo H, Raines says, “We are probing a different type of immunity. This innate immunity does not involve the immune system. It’s a way for our bodies to fight cancer without using white blood cells or antibodies—just an enzyme and a carbohydrate.”