Increasing the activity of a gene called constitutive androstane receptor (CAR), which is expressed at low levels in brain tumor stem cells, could lead to a more effective treatment for malignant glioma, according to researchers from the Methodist Hospital Research Institute in Indianapolis. The study, titled “Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells”, was published today in the British Journal of Cancer.
The scientists had set out to identify new gene targets that could be used to develop drugs for killing brain tumor stem cells. Most cancer treatments normally only target the rapidly dividing cells that make up the bulk of the tumor, while failing to tackle the more resistant cancer stem cells, the researchers say. They explain that these can start growing again at a later date, potentially explaining why glioma patients often relapse or become resistant to standard treatments.
In the search for new drug targets specific to brain cancer stem cells, the researchers compared the activity of genes in brain tumor stem cells and brain tumor cells. They focused their search on nuclear receptors, which interact directly with the DNA to control the activity of other genes and are known to be useful drug targets. This led to the discovery of a protein receptor called CAR, which is involved in processing toxins in the body.
“CAR was one of several proteins we identified that were expressed at different levels in brain tumor stem cells compared with brain tumor cells,” says John Bright, Ph.D., who led the study. “We chose to focus on CAR because we knew there was already a drug in existence called CITCO that activates this protein. So boosting the activity of CAR using CITCO could be a potent way of selectively killing brain tumor stem cells, by kick-starting the body’s normal defenses against cells dividing out of control.
“We found the drug was highly effective at killing brain tumor stem cells and brain tumor cells, without harming healthy cells, in mice and also in cells grown in the lab,” he continues.