Fingerprinting brain tumors to personalize treatment
“I can see double of everything,” 4-year-old Matthew Corrinne told his mom in November of 1991. He was watching an alphabet video, and saw two As, two Bs, two Cs. When he covered up one eye, there was one of each letter again.
Matt’s neck had been hurting on and off, recalls his mother, Cherene, and a few times he’d lost his balance and fallen off a windowsill or a kitchen countertop he’d climbed. An appointment with an eye doctor led to a CT scan that revealed a brain tumor in the cerebellum—the structure at the back of the brain that controls motor coordination, among other essential functions.
Matt had a medulloblastoma—the most common malignant brain tumor in children, and a dangerous cancer requiring aggressive treatment. Soon after he was diagnosed, the overwhelmed Corrinne family came to Children’s Hospital Boston. Neurosurgeon Michael Scott, MD, now neurosurgeon-in-chief, met them on a Thursday night. Friday, Scott and his team removed the tumor.
After surgery, Matt underwent nine weeks of chemotherapy, then six weeks of radiation of his head and spine, to try to kill off any tumor cells that lingered in the cerebellum or had spread to other parts of his central nervous system. Matt, now 23, has done well, but the aggressive treatments have carried a price. The radiation and chemotherapy left him with thinned hair, stunted growth, hearing loss and learning disabilities that have challenged him in the 19 years since his treatment. Matt’s had to work harder in school to combat cognitive difficulties, has to inject himself daily with a growth hormone and requires regular thyroid medication. Recently, he’s started to need a hearing aid.
Despite the risks associated with Matt’s aggressive treatment, at the time there really was no choice, Cherene explains. Most medulloblastoma patients receive the most aggressive course of treatment possible, because there hasn’t been a way to predict severity from case to case.
But that’s now changing. Children’s Neurologist-in-Chief, Scott Pomeroy, MD, PhD, along with neurologist, Yoon-Jae Cho, MD, and others, have made great strides toward personalizing the treatment of medulloblastoma, potentially lessening the long-term challenges that families like the Corrinnes have had to face. Early studies by Pomeroy and others showed that different patterns of gene activity in tumor samples correlate with a better or worse prognosis. Pomeroy’s team is currently conducting the largest molecular study of medulloblastoma to date, which has revealed that the tumor has six distinct varieties, each with a distinct genetic makeup—its own molecular “fingerprint.” Recognition of these tumor subtypes will allow patients who need the most aggressive treatments to get them, while patients with better prognoses can avoid them and reduce their risk for long-term physical and neurological side effects.
“We’re basically redefining the disease,” Pomeroy says. “This tumor breaks down into subtypes that really act like different diseases, and they will be treated differently looking forward.”
In addition to distinguishing tumors by their patterns of gene activity and DNA, the team also looked at about 500 microRNAs—regulatory molecules that usually dampen gene activity—and again saw distinct patterns of activity across the six different medulloblastoma subtypes. The biomarkers identified in these new findings could potentially be used to personalize treatment.
“Until recently, all we could do is look at brain tumors under the microscope, see what they look like, and knowing what part of the brain they come from, say, ‘that looks like medulloblastoma,’”Pomeroy explains. “Now we actually have precise molecular signatures. And we can say something about that subtype, what seems to be driving the tumor’s growth and what the prognosis might be.”
The new findings are expected to lead to the first use of biomarkers for medulloblastoma. The Children’s Oncology Group, an international cooperative for childhood cancer research, already plans to apply some of the new data to subtype patients in upcoming clinical trials. “We have far more samples than what was studied before,” says Cho. “Over the past two decades, Dr. Pomeroy has worked hard to accrue samples here at Children’s and to create national tumor banks that allow for this type of work.”
Matt now works in the cafeteria at Fitchburg State University. He’s a fervent sports fan and a technophile who enjoys shooting high definition video of the football games he attends. He loves to play online chess—often beating more-experienced players, like his uncles—and is a passionate advocate of practical, life skills-oriented education in high schools and colleges. He’s doing fine—but it’s been a challenging road. “Research is so important,” says Cherene.
“Thanks to Dr. Pomeroy’s team, other children who develop medulloblastoma may have an even better chance. They may be able to avoid some of the challenges that Matt has faced.”