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Two New Mutations Identified as Potential Therapeutic Targets for Glioblastoma Multiforme

Talan, Jamie

doi: 10.1097/01.NT.0000419605.77751.05
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Investigators identified the fusion of two genes — fibroblast growth factor receptor (FGFR) and transforming acidic coiled-coil (TACC), which causes chromosomal instability that leads to glioblastoma multiforme.

Scientists have discovered the fusion of two adjacent genes in some tumor cells culled from patients with glioblastoma multiforme (GBM). The finding, published in the July 26 online edition of Science, could lead to treatments that target the fused genes and slow the growth of tumor cells. There are already experimental treatments that alter the protein produced by the fused genes. Animal studies have shown that it slows the growth of brain tumor cells.

Antonio Iavarone, MD, a professor of pathology and neurology at Columbia University Medical Center and a member of Columbia's Herbert Irving Comprehensive Cancer Center, studies gene expression and transcription factors in GBM and recently began to use gene-sequencing techniques to look for genetic alterations in brain tumors. A number of gene fusions have been found in other types of cancers, specifically lymphomas and leukemias.



For the latest study, they obtained tissue from nine patients with primary GBM and grew the tumors in culture to form glioma stem cells. Then, they used sequencing techniques to look for genetic alterations. They identified the fusion of two genes — fibroblast growth factor receptor (FGFR) and transforming acidic coiled-coil (TACC). This new hybrid causes chromosomal instability, which in turn leads to GBM, said Dr. Iavarone. With this information in hand, they tested almost 100 tumor samples from GBM patients and found three percent of them had this same fusion.

The fusion constitutively activates the FGFR tyrosine kinase activity of the FGFR portion of the fusion protein, which is essential for its oncogenic function. To counter the oncogenic activity of the fusion protein, the investigators said they have successfully treated the tumor cells and the mice with inhibitors of FGFR tyrosine kinases.

“This is an extremely aberrant event,” said Dr. Iavarone. Neither gene alone has the capacity to be oncogenic. “The fusion of FGFR and TACC makes a new gene that causes chromosomal instability and transforms brain cells into cancer cells,” he added.

Co-senior author Raul Rabadan, PhD, assistant professor in the department of biomedical informatics and the Center for Computational Biology and Bioinformatics, said “sometimes errors in the DNA cause two ordinary genes to fuse into a single entity, with novel characteristics that can lead to a tumor.” His team 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.”

Dr. Iavarone and Anna Lasorella, MD, associate professor of pediatrics and pathology and a co-senior author, and their colleagues suspect that there are other genetic alterations that have yet to be identified.

They went on to conduct a series of animal studies to understand the effects of the fusion on brain cells. First, they introduced the fused genes into the brains of healthy mice and observed that aggressive brain tumors developed in 90 percent of the animals.

Then, the scientists then gave mice with these brain tumors a drug that inhibits FGFR kinase, the enzyme that is needed by the protein of the fused gene. The drug prevented the abnormal cell division and doubled survival, the Columbia team reported. It slowed the growth of brain tumors and killed tumors that were already present. The drugs work by inhibiting tyrosine kinase and blocking the function of the fusion protein, Dr. Iavarone said. These medicines, one made by AstraZeneca and Novartis, are now being tested in lung cancer patients.

The problem in getting drug companies interested in testing these types of compounds in GBM patients is doctors recruiting for such studies would have to order sequencing on every tumor to find the three percent of tumors with this genetic signature. If there are 10,000 GBM tumors a year in the US that means only 300 patients may benefit from a drug that inhibits FGFR, said Dr. Iavarone. But at a time when there are still no treatments for GBM, he said: “Even an extension of survival in 300 patients would be quite significant. We believe that this therapeutic strategy will be effective.”

Dr. Iavarone and his team collaborated with investigators around the world to carry out the current study. He is now branching out across the country to create a cooperative study group to conduct trials of the FGFR kinase inhibitors.

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“This is a pretty important finding,” said Henry S. Friedman, MD, the James B. Powell, Jr. professor of neuro-oncology and professor of pediatrics, associate professor of surgery and medicine and deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University. “These events happen in cancer but I have not seen it in GBM. The study is provocative and rigorous. It suggests a possible treatment for a small subset of GBM patients.”

Nada Jabado, MD, PhD, associate professor in the department of pediatrics at McGill University and McGill University Health Center, added that the study shows that “what is labeled under the same name glioblastoma are several distinct entities that need to be better identified to initiate proper therapy. In the case of patients carrying this fusion, identifying it in the tumor may lead to targeted therapies against FGFR-3 and improved outcome. This is probably the same for other cancers that carry the same name.”



What's more, she added: “If we don't use proper tools to better screen these tumors we will miss events like this one. It justifies the use of novel sequencing technologies of the genome, epigenome and the transcriptome in cancer to try to identify sub-group molecular entities and targetable alterations like the one identified in this study.”

“These new tools are revolutionizing the way we can detect alterations and make sense of them.” She added that more work is needed to that test whether this fused gene is a major driver in this cancer, even in the small subgroup that carries the alteration.

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• Singh D, Chan JM, Iavarone A, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012; E-pub 2012 Jul 26.
    © 2012 American Academy of Neurology