Between the blueprint of the genome and the products of its expression lie microRNAs, which can boost or lower the rate at which genes become stuff. In fact, many cancers use microRNA to magnify the expression of faulty genes or shrink the expression of helpful genes that would otherwise suppress tumors. A University of Colorado Cancer Center study published in the December issue of the Journal of Biological Chemistry shows that in medulloblastoma, a malignant brain tumor of children, microRNA-218 is especially low. The article also shows that adding microRNA-218 to neural stem cells engineered to develop medulloblastoma decreases the development of the cancer.
"For the past five years, we've been looking at microRNAs in medulloblastoma, asking how they are normally expressed and how this expression differs in the disease. One of the microRNA's most different in the medulloblastoma is microRNA-218," says Rajeev Vibhakar, MD, PhD, MPH, investigator at the CU Cancer Center, assistant professor of pediatrics at the CU School of Medicine, and the paper's senior author.
When Vibhakar and colleagues inquired into the effects of lower microRNA-218 levels, they found its involvement in pathways that signal the metabolism, growth, migration and invasion of tumor tissues. MicroRNA-218 is a tumor suppressor - low miRNA-218 equals low function in a range of tumor suppressor genes, equals high tumor growth.
In fact, the group found 618 genes whose expression was manipulated by microRNA-218.
"One of these genes was CDK6," Vibhakar says. Finding a gene target is especially important because whereas it's difficult to drug microRNA it's fairly simple to drug genes. As it turned out, Pfizer already had a drug that targets CDK6 and in a follow-up study published in the Journal of NeuroOncology, when Vibhakar and colleagues tested the drug in medulloblastoma cells, they found reduced cancer cell survival.
"Especially important is the fact that the drug led to increased radiation sensitivity in cancer cells," Vibhakar says. "Because medulloblastoma is most common in children and because high doses of radiation in children can have adverse long-term side effects, the prospect of a drug that could reduce the intensity of the required radiation is very appealing."