Discovery of Fused Genes in Brain Cancer Points to Possible Treatments
Discovery of Fused Genes in Brain Cancer Points to Possible TreatmentsResearchers have found that a small percentage of glioblastoma brain tumors, one of the most lethal forms of cancer, harbors mutations in which portions of two genes are spliced together. The researchers also showed that although the aberrant proteins produced by these fusion genes can transform normal cells into cancer cells, the actions of these fusion genes can be blocked by two experimental drugs being tested for other cancers.
Their findings, published July 26 in Science, raise the possibility that a small subset of people with glioblastoma could be treated with drugs that specifically target the fusion proteins produced by the newly identified fusion genes.
A team led by Drs. Antonio Iavarone, Raul Rabadan, and Anna Lasorella of Columbia University Medical Center found that about 3 percent of the glioblastoma tumors they examined contain FGFR-TACC fusion genes. The fusion activates a tyrosine kinase enzyme whose altered activity has been found to promote tumor growth and survival in several cancer types.
The FGFR-TACC fusion proteins "have a potent pro-tumorigenic effect," Dr. Iavarone said. "That means that when we introduce this fusion [protein] into the brain, we can transform the normal brain cells into cancer cells," he explained. When the researchers put FGFR-TACC into brain cells of healthy mice, 7 of 8 mice died of malignant brain tumors that resembled human glioblastoma.
Additional experiments showed that the FGFR-TACC fusion protein disrupts the process that apportions chromosomes between two daughter cells during cell division. This results in a condition known as aneuploidy, in which cells have an abnormal number of chromosomes. Aneuploidy is a hallmark of cancer, Dr. Iavarone noted.
Finally, the researchers showed that compounds that block the kinase activity of the fusion protein can correct aneuploidy and stop the growth of glioma cells containing FGFR-TACC. These compounds also slowed tumor growth and prolonged survival of mice with malignant brain tumors caused by FGFR-TACC. Two of the compounds, AZD4547 and BGJ398, are being tested in early-stage clinical trials for other cancers, including lung cancer.
Based on these results, "we believe that there is a strong rationale to do a clinical trial where we would target tumors that harbor these gene fusions with these drugs," Dr. Iavarone said. He and his colleagues in the United States and Europe have formed a cooperative research group and begun talks with the drug manufacturers in hopes of moving forward with such a trial.
Further reading: "Common Cancers May Involve Fused Genes"
This research was supported by grants from the National Institutes of Health (R01CA101644, R01CA131126, R01CA085628, R01CA127643, U54 CA121852-05,1R01LM010140-01, R01NS061776).