Transforming fusions of FGFR and TACC genes in glioblastoma
Study pinpoints that a genetic cause of glioblastoma may lead to new treatments
- Date : 01 Aug 2012
- Topic : Head and neck cancers
Researchers at Columbia University Medical Center have discovered that some cases of glioblastoma, the most common and aggressive form of primary brain cancer, are caused by the fusion of two adjacent genes, fibroblast growth factor receptor (FGFR) and transforming acidic coiled-coil (TACC). The preclinical study also found that drugs that target the protein produced by this genetic aberration can dramatically slow the growth of glioblastomas. The findings were published last week in the online edition of the journalScience.
According to study leader Dr Antonio Iavarone, who is a professor of pathology and neurology at Columbia University Medical Center, and a member of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital, from a clinical perspective, his team has identified a druggable target for a brain cancer with a particularly dismal outcome. From a basic research perspective, they have found the first example of a tumour-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 tumours.
The fusion of these two genes was observed in just 3% of tumours studied, so any therapy based on this
particular genetic aberration would apply to only a small subset of glioblastoma patients. It's unlikely that the researchers will find a gene fusion responsible for most glioblastomas. But they may be able to discover a number of other gene fusions, each accounting for a small percentage of tumours, and each with its own specific therapy.
A protein produced by FGFR-TACC acts by disrupting the mitotic spindle
Glioblastomas is invariably fatal, with a median survival of about 14 months after diagnosis, even with aggressive therapy. Several common single-gene alterations have been observed in glioblastoma. However, therapies targeting these alterations have not improved clinical outcomes, most likely because they have systematically failed to eradicate the proteins to which the tumour is 'addicted.
Dr Iavarone and his colleagues suspected that glioblastomas might be addicted to proteins produced by gene fusions. Such fusions have been implicated in other malignancies, notably chronic myelogenous leukemia (CML). Imatinib, which
targets a fusion protein responsible for CML, has proved to be highly effective in arresting the disease.
In the current study, the researchers conducted genetic analyses of glioblastomas from nine patients, looking specifically for gene fusions. The most common fusion they observed involved the genes FGFR and TACC. 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 tumour.
The researchers developed a new method for analysing the cell's genomic material. First they looked at pieces of the glioblastoma genome from several samples, and then they extended the analysis to a large set of glioblastomas from the Cancer Genome Atlas project, sponsored by the USA National Cancer Institute.
The study team discovered that the protein produced by FGFR-TACC acts by disrupting the mitotic spindle, the cellular structure that guides mitosis. If this process happens incorrectly, it leads to aneuploidy, which is thought to be the hallmark of tumourigenesis.
When FGFR-TACC was introduced into the brain cells of healthy mice, aggressive brain tumours developed in 90% of the animals, confirming that this gene fusion can lead to glioblastoma. In another experiment, mice with this form of glioblastoma were given a drug that inhibits FGFR kinase, an enzyme essential for the protein produced by FGRF-TACC. The drug was found to prevent abnormal mitosis and double survival time, compared with a control group of mice that did not receive the drug.
Conducting trials with FGFR kinase inhibitors
Dr Iavarone is currently establishing a cooperative study group, including his and other brain tumour centres around the USA, to conduct the trials of FGFR kinase inhibitors. Preliminary trials of these drugs, for treatment of other forms of cancer, have shown that they have a good safety profile, which should accelerate testing in patients with glioblastoma.
This work is the result of an ongoing collaboration between a traditional and a computational lab. The synergy between the two approaches allows to tackle complex biological problems in a high throughput fashion, providing a global view to the genome of glioblastoma, according to Dr Raul Rabadan, assistant professor in the department of Biomedical Informatics and the Center for Computational Biology and Bioinformatics, Columbia Initiative in Systems Biology.
The other study contributors are researchers from Weill Cornell Medical College, New York, USA; Fondazione I.R.C.C.S Istituto Neurologico C. Besta, Milan, Italy; Bioinformatics Center, BGI, Shenzhen, China; Biogem, Ariano Irpino (AV) and Dipartimento di Scienze Biologiche ed Ambientali, Università del Sannio, Benevento, Italy; Catholic University, Rome, Italy; Emory University School of Medicine, Atlanta, USA; University of Toronto, Toronto, Canada; M.D. Anderson Cancer Center, Houston, USA; NYU Langone Medical Center, New York, USA; and Henry Ford Health System, Detroit, USA.
This research was supported by the USA National Cancer Institute grants R01CA101644, R01CA131126, R01CA085628, R01CA127643, and U54 CA121852-05; National Library of Medicine grant 1R01LM010140-01; National Institute of Neurological Disorders and Stroke grant R01NS061776; Partnership for Cure grant 7-78947; and grants from the Chemotherapy Foundation, the Associazione Italiana per la Ricerca sul Cancro, and the Italian Ministry of Health. Additional support was provided by Giuseppe Bruno, Marianne Mebane, and Denise and David Chase.
Otherwise, the authors declare no financial or other conflicts of interest.
Drs Iavarone, Lasorella, and Rabadan and Columbia University Medical Center have filed a patent application related to the diagnostic and therapeutic use of FGFR-TACC gene fusions.
Caption:FGFR-TACC fusion protein disrupts cellular division (mitosis) by localising aberrantly at the mid-body of dividing cells. Here, FGFR-TACC (shown in red) can be seen interacting with tubulin bundles (green), structures that support mitosis, at the point connecting the two daughter cells (whose nuclei are colored blue).
Caption:This shows an abnormal accumulation of the FGFR-TACC fusion protein (red) in glioblastoma stem cells isolated from a primary human glioblastoma with fused FGFR- TACC genes. Cellular nuclei are colored blue.
Caption:This is a graphic representation of the collaboration between experimental and computational biology. The outer ring represents results of next-generation genetic sequencing of the glioblastoma genome, showing expression of the FGFR-TACC fusion gene (red peaks). In the center, FGFR-TACC fusion protein (red) can be seen disrupting tubulin bundles (green), structures that support cell division, or mitosis, at the point connecting the two daughter cells (whose nuclei are colored blue).
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