Carbone Cancer Center Finds a New Biomarker for Fatal Brain Cancer
Madison, Wisconsin — A whimsically named gene coding for an ion channel associated with irregular heart rhythm risk may also help predict survival in patients with the most malignant type of brain cancer, according to new research from the University of Wisconsin Carbone Cancer Center.
Patients with this cancer, glioblastoma (GBM), generally live less than two years; it is the type of brain cancer that killed Beau Biden and Sen. Edward Kennedy.
Dr. John Kuo, who heads the Carbone brain tumor program, and lead author Dr. Kelli Pointer, found that GBM tumors expressing higher levels of the human Ether-à-go-go Related Gene (hERG) tend to grow more quickly, and these patients had shorter survival. But if they received drugs that also incidentally block the hERG potassium channel, they had better survival.
This research study was a featured article in the January issue of Clinical Cancer Research, published by the American Association of Cancer Research. It was published with an accompanying commentary highlighting the significance of the findings.
What made neuroscientists look for a gene known to make anesthetized fruit flies kick their legs like go-go dancers? The answer, like a lot of science, began over a beer.
First some background: The Ether-à-go-go Related Gene, studied by Dr. Barry Ganetzky, now professor emeritus at UW-Madison, was so named because fruit flies with mutations in this gene kicked their little legs like go-go dancers when anesthetized with ether. The hERG gene is a human version of the gene. In humans, scientists later learned that hERG is associated with heart problems that can cause fainting and sudden death.
Co-author Dr. Gail Robertson, a former member of the Ganetzky lab and now UW-Madison professor of neuroscience, explains that the gene encodes a potassium channel that regulates electrical impulses in cells. She discovered that hERG potassium channels were the target for some drugs – ranging from sedatives to cancer medicines – that jam the channel in heart cells, causing heart arrhythmia and death.
This research led to new safety tests to reduce the risk that new drugs in development would cause sudden cardiac death and prevent the expensive withdrawal of drugs, like Seldane for allergies and Darvon, a pain drug, from the market.
Now comes the part with the beer. At a party for new graduate students, Robertson mentioned that hERG is also expressed in some glioblastomas, sparking Pointer’s interest in this gene. So as a side project in the Kuo laboratory, Pointer, who earned a PhD and is now finishing her medical degree through the UW School of Medicine and Public Health's Medical Scientist Training Program, decided to analyze glioblastoma tumors for the presence of hERG. They checked whether hERG expression correlated with tumor proliferation after implanting glioblastoma cancer stem cells into mouse brains, and cross referenced the results with tumor samples from 115 brain cancer patients.
Once the tumors were analyzed, Kuo and Pointer found that glioblastoma that expressed higher levels of hERG proliferated more rapidly. Those patients also had shorter survival. Their survival averaged 43.5 weeks compared with 60.9 weeks for patients whose tumors only weakly expressed the gene.
But remember those drugs known to also block hERG? Not all are dangerous, and in fact some are prescribed as highly effective anti-seizure or anti-psychotic medications. Some patients were treated with anti-seizure drugs (with incidental hERG-blocker activity) following brain tumor surgery.
A sub-group analysis showed those drugs improved survival in patients with high hERG expressing tumors, but made no difference in survival for low hERG-expressing GBM patients.
“Our findings suggest that hERG is a potentially powerful GBM biomarker,” says Kuo, associate professor of neurosurgery. “The data also suggest the possible rapid application of drugs already approved by the FDA that inhibit this ion channel to benefit GBM patients.”
Since this study was looking backward at how patients fared, the next step could be a prospective clinical study to assess whether the subset of GBM patients with hERG-positive tumors directly benefit from drugs known to block hERG potassium channels.
Robertson says several laboratories are studying the role that hERG plays in cancer. And while cancer is not her main interest, she enjoyed collaborating with Pointer and the Kuo lab.
“I jumped at the chance to be involved,” Robertson says. “It’s not often you get to interact across the disciplines of neuroscience and cardiac arrhythmias. But when you get a great student like Kelli, it really brings faculty together.”
Date Published: 01/25/2017