Two Genes That Drive Aggressive Brain Cancers Discovered

A team of Columbia scientists have discovered two genes that, when simultaneously activated, are responsible for the most aggressive forms of human brain cancer.

This finding was made possible by the assembly of the first comprehensive network of molecular interactions that determine the behavior of these cancer cells, a map so complex and elusive that, until now, it could not be constructed. The discovery may lead to completely novel strategies to diagnose and treat these incurable tumors.

The findings will be published in an advanced online edition of Nature on Dec. 23, 2009, by a team of Columbia scientists led by Antonio Iavarone, M.D., associate professor of neurology in the Herbert Irving Comprehensive Cancer Center, and Andrea Califano, Ph.D., director of the Columbia Initiative in Systems Biology.

The researchers studied a type of human malignancy, called glioblastoma multiforme, which is among the most lethal because it rapidly invades the normal brain producing inoperable brain tumors. Recently, glioblastoma claimed the life of Senator Edward Kennedy only sixteen months after diagnosis.

Before this study, cancer researchers had little idea why glioblastoma is so aggressive. “We now know that two genes – C/EPB and Stat3 – are the disease’s master ‘control knobs’,” said Dr. Iavarone. “When simultaneously activated, they work together to turn on hundreds of other genes that transform brain cells into highly aggressive, migratory cells.”

The two genes are active in about 60 percent of all glioblastoma patients and help identify poor-prognosis patients. All patients in the study whose tumors showed activation of both factors died within 140 weeks after diagnosis, while one half of the patients without these factors were still alive.

“The finding means that suppressing both genes simultaneously, using a combination of drugs, may be a powerful therapeutic approach for these patients, for whom no satisfactory treatment exists,” said Dr. Califano.

This approach, called combination therapy, is supported by this study since silencing both genes in human glioblastoma cells completely blocked their ability to form tumors when injected in a mouse. Based on these results, the Columbia scientists received a grant from the American Recovery and Reinvestment Act to develop drugs specifically aimed at these genes.

Two Genes Uncovered with a Systems Biology Approach

Biomedical researchers today are like city engineers trying to reduce traffic jams without a street map. Armed only with a list of congested roads, engineers would not be able to locate the traffic jams or find the best way to unclog them. But with a city map in hand, clusters of congestion would immediately become apparent along with possible solutions.

“We are fighting very much the same problem in the post-genomic era,” said Dr. Califano. “The human genome project has given biologists a wonderfully comprehensive list of street names – the genes inside every human cell. Unfortunately, it provided virtually no understanding of how all those genes may work together, within highly complex control networks, to operate the cell. In short, biologists need a map of the cell.”