Feature: Finding new ways to treat leukemia after relapse
By Crystal Mackay, MA'05
Acute lymphoblastic leukemia is the most frequently occurring type of cancer in young children. While cure rates are now better than 90 per cent, success rates are poor in cases where the disease relapses or comes back after treatment.
A research team led by Rodney Dekoter, PhD, is working to understand what is causing this to occur in order to pinpoint better, more effective treatments after relapse.
“One of the characteristics of this cancer, is that sometimes after treatment, it relapses and comes back again. What doctors have found throughout the years is that when patients relapse, they have different mutations in these cancer cells than the first time the cancer occurred,” said Dekoter, Professor in Microbiology and Immunology at Schulich Medicine & Dentistry. “The question is what is the cause of those mutations and where are they coming from?”
In a new study published this month in Molecular and Cellular Biology, Dekoter and his team used genetically modified mice to show that the mutations are caused by DNA damage that is ongoing in the cancer cells. They also demonstrated that that this DNA damage can be disrupted.
The team looked specifically at a family of proteins called janus kinases. “These kinases are named for the two-faced Roman god, Janus,” said Dekoter. “Mutations in the ‘good’ domain of these proteins lead to dysregulation allowing the ‘bad’ domain to dominate and cause disease.”
In order to determine the role of janus kinases in leukemia, the researchers treated mouse models with a drug that inhibits these proteins. Dekoter describes the drug as the ‘monkey wrench’ in the kinases’ molecular machine. The drug, called Ruxolitinib, fits right into a pocket in the Janus Kinase machinery and stops it from working.
The drug is approved for treating very specific blood disorders and is in clinical trials for its role in treating leukemia.
As expected, the research team found that the mice treated with Ruxolitinib were greatly delayed in developing leukemia compared to mice not treated with the drug. They also found disruption in the DNA damage in the mice treated with the drug, a finding they hadn’t anticipated.
“Unexpectedly, we found that the pattern of mutations was also changed in the cancer cells of the mice treated with the drug. This indicates that janus kinases also play a role in the DNA damage that causes the mutations in the cancer cells,” said DeKoter.
This information is key in understanding the cause of the mutations in these cancer cells after relapse, and also provides a potential for improved treatment for acute lymphoblastic leukemia.
“Our hope is that this will help to point to treatments that will not only kill the leukemia cells, but prevent them from coming back. This looks promising because it is an unexpected mechanism of action of a drug that is already being tested in clinical trials for leukemia,” he said.
