WebMD Medical News
Laura J. Martin, MD
Dec. 22, 2010 -- Scientists say they’ve discovered a genetic defect that may contribute to the development of as many as one in four cases of glioblastoma, the most common and aggressive type of brain tumor.
The defect, a deletion in a gene known as NFKBIA, prevents cells from making enough of a protein that acts as a natural tumor suppressor.
Without the protein, called I-kappa-B, cancer cells become particularly aggressive and difficult to kill.
The study, which was published online Wednesday in The New England Journal of Medicine, found that patients with the NFKBIA deletion had significantly worse responses to treatment and much shorter survival times than those whose tumors did not have the defect.
When researchers boosted levels of I-kappa-B in cancer cells, however, the cells became more sensitive to a chemotherapy drug, giving researchers hope that they’d found a kind of biochemical Achilles’ heel for this kind of tumor, which is nearly always fatal.
“Unfortunately, glioblastoma is one of the most aggressive of human tumors, the median survival for patients with glioblastoma has not changed substantially since we started radiation many years ago, so there’s an urgent need to find therapies that prolong outcomes in these patients,” says Kenneth D. Aldape, MD, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston, who was a co-author on the study.
“This provides the first step for a targeted therapy for a subset of patients with glioblastoma,” he says.
For the study, researchers tested 790 human glioblastoma brain tumors for defects in the NFKBIA gene and for abnormalities in a related, previously known gene that codes for epidermal growth factor receptor, or EGFR.
Researchers found that about one in four tumors carried the NFKBIA deletion. The EGFR glitch was present, as other studies had found, in about one-third of these tumors.
Only about 5% of all tumors carried both defects, indicating that the two genes, which affect the same biochemical pathway, may be responsible for about 60% of these kinds of brain tumors.
“In the majority of the cases, one of these two genes or abnormalities in these genes contributes significantly to the malignant behavior of these cells,” says senior author Griffith Harsh, MD, professor of neurosurgery at the Stanford University School of Medicine.
Researchers also found that having defects in one or both of the genes significantly decreased survival.
In a group of 171 patients in the study diagnosed with glioblastoma, for example, those with the NFKBIA deletion had a median survival time of 46 weeks, and those with the EGFR amplification had a median survival of 53 weeks, compared to about 67 weeks for people without either abnormality.
The discovery of the NFKBIA gene and how it contributes to this kind of cancer may soon allow doctors to test patients for the gene and give them treatments that may correct for the genetic deficiency.
“The home run will be if we can identify patients with this defect and find out if a neutralization of this pathway actually helps them,” Aldape says.
There’s already some evidence that such a strategy could work.
The new study also found that boosting the expression of I-kappa-B in cancer cells that carry the NFKBIA deletion makes them more vulnerable to a chemotherapy drug called Temodar.
There’s a study already under way at Northwestern University that is testing a drug called Velcade, which helps to stabilize levels of the I-kappa-B protein in cancer cells.
The hope is that Velcade, or another as-yet-undiscovered medication, could first be given to patients to help sensitize cancer cells to a next wave of chemotherapy or radiation treatments that could then finish them off.
If that happens, experts say it could be the first real spark of hope in a cancer where diagnosis is nearly always a death sentence.
“I’ve been focusing on brain tumors for one-quarter of a century,” says Harsh, “and it’s heart wrenching to lose patient after patient.”
SOURCES:Griffith Harsh, MD, professor of neurosurgery, Stanford University School of Medicine.Kenneth Aldape, MD, professor of pathology, University of Texas M.D. Anderson Cancer Center.Bredel, M. New England Journal of Medicine, published online Dec. 22, 2010.
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