A Urine Test for Brain Tumors?
By Parizad Bilimoria
A urine sample can tell you many things. It can reveal pregnancy, signal an infection or unmask drug use. Could it also tell you about brain tumors?
Maybe. Researchers at Children’s Hospital Boston are hoping that urine tests will one day facilitate the diagnosis of neurological conditions.
Image-based screening for brain tumors and other central nervous system diseases is time-consuming, costly and poses some risk—especially for young patients who require sedation to hold still in the scanner. The ordeal is multiplied for children who have had brain surgery and need frequent checks for disease resurgence. Adding to these factors, many families do not live near medical centers with pediatric neuroimaging facilities.
This is why Edward Smith, MD, Director of Pediatric Cerebrovascular Surgery, is on a quest for easily detectable biomarkers for brain disease—molecules whose presence in the urine might aid in diagnosing and assessing the status of brain cancers. Excluding trauma, brain tumors are the most common solid cancer of childhood and the leading cause of death of children.
“Right now, we take kids, and every three months—when we know they have a tumor—put them under anesthesia, place them in a freezing cold scanner and then take a study for thousands of dollars to see if there’s a growth there,” says Smith.
When Smith first came to Children’s, he attended a seminar by Marsha Moses, PhD, director of the Vascular Biology Program. Moses studies the process of angiogenesis, the growth of new blood vessels, during cancer. Her laboratory has pioneered the use of matrix metalloproteinases (MMPs) as biomarkers for breast and ovarian cancer. MMPs are enzymes that help tumors eat through the dense material that surrounds cells, allowing new blood vessels to sprout.
Smith was intrigued by Moses’s idea of focusing on biomarkers in urine instead of blood. From a biochemical standpoint, working with urine can be advantageous, because the kidneys filter out many proteins for which a blood test would be unreliable, since their levels in blood are highly variable.
After the seminar, Smith asked Moses whether it might be worth looking in the urine to diagnose brain disease. After all, the brain cancers and neurovascular conditions that Smith treats use the process of angiogenesis to invade normal brain tissue—not unlike breast or ovarian tumors.
Moses offered Smith a chance to work in her lab. In 2008, they reported the first panel of urinary biomarkers for brain tumors, showing that certain angiogenesis proteins (vascular endothelial growth factor, MMP-2, MMP-9 and MMP-9/neutrophil gelatinase-associated lipocalin) predicted the presence or absence of a tumor. The urinary levels of these biomarkers correlated with their levels in the tumor tissue, and surgical removal of tumors resulted in the clearance of these proteins from the urine.
As Smith did his experiments, he was motivated by the case of an eight-year-old girl he had seen. She had made a doctor visit for gastrointestinal complaints, at which no serious problems were found, but she ended up needing emergency brain surgery.
A routine urine test at the GI appointment showed unusually high levels of MMPs, but since the MMP research was still ongoing, the finding was not used to direct the girl’s care. However, it was noted in her medical records that a couple of years prior she had been successfully treated for a brain tumor.
A month after the urine test, the girl developed severe headaches and vision difficulties. In the emergency room, MRIs revealed that her brain tumor had come back, and was pressing against the major vision nerves at the base of the brain.
Fortunately, Children’s neurosurgical team was able to remove the tumor, and her vision was saved. “She did fine, thankfully,” Smith says. But the MMP question fascinated him.
“Had we been smart enough to act on that biomarker when she was not symptomatic, could we have treated this before her vision was at risk?” he asks. “This single case study really highlighted how useful urinary biomarkers could be.”
Smith’s team is now planning a clinical trial to study the efficacy of the biomarkers he and Moses identified by following patients over at least two to three years, from initial diagnosis well into the post-surgery recovery phase. Levels of specific biomarkers will be correlated with the presence or absence of tumors on brain scans, the current gold standard for diagnosing tumors and predicting their resurgence after removal. A major goal will be to determine whether these biomarkers identify tumors earlier, later or at the same time as the brain scans.
Could biomarkers distinguish among different types of brain tumors? They might, says Smith. Certain markers may be unique to certain brain tumor types, or their relative amounts might differ from tumor to tumor in a predictable fashion—providing a molecular “fingerprint” for distinguishing the tumor variety.
The goal of developing urinary biomarkers is not to replace imaging studies, Smith says, but to decide whether a brain scan is necessary, or to provide information complementing the scan. “The strength of this approach is not to look at a urine test and say, ‘Oh, you have a three-centimeter right cerebellar medulloblastoma that’s starting to spread,’ but rather to say ‘You’ve got something funny going on—we should get a scan,’” he explains.
Aside from diagnostics, another important reason to study tumor fingerprints is to identify possible molecular culprits to go after in order to destroy the tumor. “I’m interested in using this technique not just in developing an early warning system, is something we really need in neurosurgery,” Smith says, “but also to identify potential therapeutic targets.”