A new study by Columbia University’s Medical Center (CUMC) researchers shows that some cases of glioblastoma, a very common and aggressive form of primary brain cancer, are caused by the fusion of two adjacent genes.
The study, published online in the journal Science, also found that the growth of glioblastoma in mice could be significantly slowed down by drugs, which target the protein that is produced by these two adjacent genes.
Leading researcher, Antonio Iavarone, MD, professor of pathology and neurology at CUMC, and a member of the Herbert Irving Comprehensive Cancer Center (HICCC) at the NewYork-Presbyterian Hospital/Columbia University Medical Center declared:
“Our findings are doubly important. From a clinical perspective, we have identified a druggable target for a brain cancer with a particularly dismal outcome. From a basic research perspective, we have found the first example of a tumor-initiating mutation that directly affects how cells divide, causing chromosomal instability. This discovery has implications for the understanding of glioblastoma as well as others types of solid tumors.”
The researchers observed the fusion of these two genes in only 3% of the studied tumors, meaning any treatments for this particular genetic abnormality would only apply to a small number of glioblastoma patients.
Co-senior author, Anna Lasorella, MD, associate professor of pathology and pediatrics at CUMC and a member of the Columbia Stem Cell Initiative and the HICCC, said: “It’s unlikely that we will find a gene fusion responsible for most glioblastomas. But we may be able to discover a number of other gene fusions, each accounting for a small percentage of tumors, and each with its own specific therapy.”
Stephen G. Emerson, MD, PhD, director of the HICCC and the Clyde ’56 and Helen Wu Professorship in Immunology at the Columbia University College of Physicians and Surgeons added: “This is a very exciting advance in our understanding of cancer, and perhaps a first step toward a personalized, precision approach to the treatment of glioblastoma.”
Glioblastomas are tumors caused by astrocytes, star-shaped cells that make up the brain’s supportive tissue. Glioblastomas are generally highly malignant because these astrocytes reproduce rapidly and are supported by a large network of blood vessels.
Around 10,000 people in the U.S. suffer from glioblastomas, which is generally treated by surgery, radiation and chemotherapy. Those diagnosed with glioblastomas have an average survival ratel of 14 months after diagnosis. However, even with aggressive therapy the disease is invariably fatal.
A few famous people who died from glioblastomas include Senator Edward Kennedy, who died from the disease in 2009, and New York Mets all-star catcher Gary Carter in 2012.
Although researchers have observed several common single-gene alterations in glioblastoma, Dr. Iavarone said: “However, therapies targeting these alterations have not improved clinical outcomes, most likely because they have systematically failed to eradicate the proteins to which the tumor is ‘addicted.'”
Dr. Iavarone and his team hypothesized that glioblastomas might be addicted to proteins produced by gene fusions, which have been involved in other cancers, particularly in chronic myelogenous leukemia (CML). One drug that has proved to be highly effective in stopping the disease from progressing is Gleevec (imatinib) produced by Novartis, which targets a fusion protein responsible for CML.
For the new study, the CUMC team genetically analyzed glioblastomas from 9 patients to search specifically for gene fusions. They found the genes FGFR, a fibroblast growth factor receptor, and TACC, a transforming acidic coiled-coil, were the most frequent genes involved in fusion.
Co-senior author Raul Rabadan, PhD, an assistant professor in the department of Biomedical Informatics and the Center for Computational Biology and Bioinformatics at the Columbia Initiative in Systems Biology said:
“Although each gene plays a specific role in the cell, sometimes errors in the DNA cause two ordinary genes to fuse into a single entity, with novel characteristics that can lead to a tumor. We developed a new method for analyzing the cell’s genomic material. First we looked at pieces of the glioblastoma genome from several samples, and then we extended the analysis to a large set of glioblastomas from the Cancer Genome Atlas project, sponsored by the National Cancer Institute.”
The team noted that the protein produced by FGFR-TACC works by disrupting the mitotic spindle, which controls mitosis. The mitotic spindle is the cellular structure that guides mitosis, i.e. the division of a cell into two identical daughter cells. Dr. Iavarone said: “If this process happens incorrectly, you get uneven distribution of the chromosomes. This condition, which is known as aneuploidy, is thought to be the hallmark of tumorigenesis.”
The team was provided with evidence that this gene fusion can lead to glioblastoma when they introduced FGFR-TACC into brain cells of healthy mice, and observed that 90% of the animals developed aggressive brain tumors. They conducted another experiment, administering glioblastoma mice with the abnormal formation of genes a drug that blocks FGFR kinase, which is a vital enzyme for the FGRF-TACC-produced protein to function. They noted the drug could prevent abnormal mitosis and raise the animals’ survival time by 50% compared with mice in a control group that were not given the drug.
At present, Dr. Iavarone is in the process of establishing a cooperative study group, which includes CUMC and other nation-wide brain tumor centers, to perform trials of FGFR kinase inhibitors. Preliminary trials of these drugs for the treatment of other forms of cancer have demonstrated that the drug has a good safety profile, which means that tests in patients with glioblastomas could potentially be accelerated.
Dr. Rabadan concludes: “This work is the result of an ongoing collaboration between a traditional and a computational lab. The synergy between the two approaches allows us to tackle complex biological problems in a high throughput fashion, providing a global view to the genome of glioblastoma.”
Written by Petra Rattue