Turning the tide

Turning the tide

Clinicians and researchers chart a course to find cures for high-grade gliomas.

As Noah Shumate bounded onto a blustery South Carolina beach last December, he beheld an expansive panorama of sand, surf and seagulls. To the excited 3-year-old, the possibilities seemed as endless as the horizon.

But two days later, his family’s idyllic vacation plans collapsed like a sandcastle at high tide.

When Noah’s right eye suddenly began to cross, Billie and Richard Shumate rushed him to a local hospital. A scan revealed a tumor deep within Noah’s brain. After further testing at another hospital, a pediatric oncologist asked to speak privately with the couple.

“Our world shattered,” recalls Billie, who is a nurse. “The doctor said that Noah had an inoperable brain tumor called a pontine glioma. She told us that there was no treatment for it and that Noah had about six months to live.” The physician suggested that the Shumates make hospice arrangements for their younger son.

Reeling with shock, Billie spoke to her aunt, who encouraged the couple to have their physician obtain a referral to St. Jude Children’s Research Hospital.

“She told me not to give up hope,” Billie recalls.

The morning after requesting the referral, Billie phoned St. Jude.

“I didn’t give my name or Noah’s name to the lady who answered,” she says, “But as soon as I mentioned that my son had a pontine glioma, she said, ‘Is his name Noah?’ My heart began to race, because I knew God was going to take care of us.”

Turbulent seas

Noah’s brain tumor is a type of high-grade glioma known as diffuse intrinsic pontine glioma (DIPG). High-grade gliomas are malignant tumors that arise from glial cells in the brain or spine. When a high-grade glioma originates in the brainstem, the tumor is known as DIPG. Fewer than 30 percent of children with high-grade gliomas survive the disease. For patients with DIPG, survival rates are even more dismal, hovering below 10 percent.

“Survival is tied to how much of the tumor can be surgically removed,” explains Alberto Broniscer, MD, of St. Jude Oncology. Unfortunately, DIPGs are entrenched in the middle of the brainstem and entangled among the nerves.

“If you have a high-grade glioma in another part of the brain, you can remove more of it,” Broniscer says. “With a DIPG, you can remove little, if any, of it.”

Despite the diagnosis, the Shumates were heartened after meeting Broniscer.

“He was positive and optimistic about the course we were going to take in treating this tumor,” Billie recalls. “Dr. Broniscer said Noah would begin a six-week run of radiation treatments five days a week. He’d also take two forms of chemotherapy for two years. Hopefully, the radiation would shrink the tumor as much as possible and the chemo would kill off the remaining tumor cells.”

All hands on deck

St. Jude researchers and clinicians have been teaming up to battle high-grade gliomas for years.

“In the past, the standard treatment for DIPG was irradiation—that’s all,” Broniscer observes. But teams of St. Jude clinicians and laboratory scientists have been focusing their efforts on finding new and more effective treatments for DIPG and other high-grade gliomas. Investigators have been exploring different methods of killing the tumors. These techniques range from treatments that cut off the tumor’s blood supply to medications that block the receptors instructing brain tumor cells to divide and grow.

Several years ago, St. Jude opened the world’s first clinical trial to use irradiation and a drug called vandetanib to treat children with DIPG. Broniscer and Suzanne Baker, PhD, of St. Jude Developmental Neurobiology are also collaborating on a biologic study of DIPG tumors. The investigators have collected 43 samples of the tumor and are performing molecular analyses on the samples to gain a better understanding of DIPG’s genetic make-up.

In another study, Baker, Broniscer and their colleagues recently published the most comprehensive analysis to date of the genetic mutations driving pediatric high-grade gliomas.

The investigators evaluated DNA from 78 tumors, looking for additions or deletions in the genetic material. Using advanced technology, they scrutinized more than 500,000 points across the genome. For 53 of the 78 samples, scientists also evaluated gene activity and compared the results with data from adult tumors.

“We were hoping to find patterns of abnormalities that happen over and over again in multiple tumors,” Baker explains. “That would tell us which genes, when disrupted in a certain way, can make the cell lose control and transform itself from a normal cell into a tumor cell.”

Uncharted waters

Although high-grade gliomas occur in both adults and children, investigators found that vastly different mutations drive the disease processes. A gene called PDGFRA is crucial in development of the childhood disease, whereas the EGFR gene is the most important culprit in the adult form. Baker and her colleagues were exhilarated when they found the link to PDGFRA, because a drug called dasatinib had already been developed to target that receptor.

“This is a perfect example of how exciting it is to work at St. Jude,” Baker says. “In many places a basic researcher would have difficulty quickly translating a lab discovery into the clinic. But when we found that PDGFRA was important and that a drug was already available, I called Alberto Broniscer and Amar Gajjar [co-leader of the St. Jude Neurobiology and Brain Tumor Program] and told them about it. Before our paper was even published, Alberto Broniscer had a clinical trial open to test dasatinib. I don’t know of anywhere else where that could happen so efficiently.”

In the new DIPG clinical trial, St. Jude clinicians administer vandetanib and dasatinib along with radiation therapy. Tests conducted elsewhere on adults indicated that each of these medications can cause some types of cancer to shrink or stop growing. The hospital conducted a previous treatment combining irradiation and vandetanib in children with DIPG. However, the St. Jude protocol marks the first time this drug combination has been tested with irradiation in children and adolescents.

Secrets of the deep

Noah’s parents enrolled him in the new DIPG protocol in December 2009. Scans performed earlier this year showed that his tumor had decreased by 60 percent. “We were thrilled,” says Billie, who realizes that challenges still lie ahead.

Meanwhile, clinicians and researchers at St. Jude continue their quest to better understand high-grade gliomas.

“Every time you answer one question, many new interesting ones come up,” Baker observes. “For instance, there are a lot of things we don’t know about drugs that target PDGFR: Are they optimal? Will they cross the blood/brain barrier efficiently? Do they need to do that to be effective for DIPG? If a tumor is driven by this abnormal protein, can we merely block the activity of that protein and stop the tumor, or will we need to combine that therapy with something else? What combinations are most likely to succeed?”

St. Jude researchers are now conducting functional studies for PDGFRA, which include developing markers to test how well the drug blocks the receptor in laboratory models.

On the horizon

Somewhere amid all those queries lie answers that may offer hope to children and adolescents with high-grade gliomas. The rate that technology is moving may accelerate that discovery process.

“In the project we recently completed, we used technology that is still relatively new,” Baker says. “This study couldn’t have been done five years ago in the same way; it couldn’t have been done even three years ago in the same way. We’re currently doing a similar analysis on diffuse pontine glioma, and we’re using the next generation of technology, which gives more than double the information we had for our previous high-grade glioma study.”

In spite of the rapid technological advances, Broniscer emphasizes that progress is usually incremental.

“You know the story of leukemia treatment at St. Jude,” he says. “They didn’t move from a 10 percent to 90 percent survival rate in a single shot. With every study, we learn a little more about these tumors.”

Each discovery provides the basis for another question and yet another discovery. As scientists and clinicians continue their research, they can gain inspiration from patients like 4-year-old Noah, who pursues his own important projects with energy and single-minded enthusiasm. With his condition currently stable, Noah spends his days romping with his dogs, riding his big brother’s quarter horse, playing T-ball and swimming in his grandparents’ pool. During the summer of 2010, he and his family also vacationed at another beach—a place of blue skies, shimmering sand and a horizon of boundless possibilities.

Reprinted from Promise Autumn 2010

Editor's note: Noah passed away in September 2011.

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