Santiago Buther is taking part in the study. “For us, this drug seemed to give him the best everyday life along with the best fighting chance to go after the tumor,” explains Santiago’s dad, Eric.

 
 

DIPG: Focused Steps

St. Jude clinical trial tests chemotherapy that crosses the blood-brain barrier to reach a deadly brain tumor.

By Maureen Salamon; Photos by Ann-Margaret Hedges and Peter Barta

Whether he’s dancing to his favorite music or sprinting across a soccer field with his friends, Santiago Buther shows single-minded determination. On the playing field, he spares no effort to beat his buddies at their favorite game. As a dancer, the 8-year-old boy responds viscerally to the pounding beat.

So, it’s no surprise Santiago is facing his biggest foe head-on: a brainstem tumor known as DIPG, or diffuse intrinsic pontine glioma. Radiation treatment at St. Jude Children’s Research Hospital helped restore Santiago’s physical prowess — and his smooth dance moves — after effects of the rare tumor forced him to use a wheelchair.

 

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Amar Gajjar, MD

Taking aim at DIPG:
Amar Gajjar, MD, Pediatric Medicine chair, and his colleagues are leading a study that features a new chemotherapy drug. This drug targets a growth pathway that is overactive in most DIPGs and similar brain tumors.

He’s also part of a St. Jude clinical trial that aims to push DIPG treatment — which hasn’t significantly advanced in more than 50 years — a major step forward. The study, called SJPI3K, is testing a new chemotherapy drug. The drug targets a growth pathway that is overactive in most DIPGs and similar brain tumors. But unlike most other chemotherapies, this medication also crosses the blood-brain barrier, helping deliver its potent effects straight to malignant cells.

“For us, this drug seemed to give him the best everyday life along with the best fighting chance to go after the tumor,” says Santiago’s dad, Eric Buther.

In these walls, it feels like they only care about the children and a cure.

Eric Buther

 
 

New options

The trial will include about three dozen St. Jude patients who have newly diagnosed DIPG or similar tumors. About 250 children in the United States are found to have this disease each year. It has a dire prognosis: Patients survive only nine to 12 months on average, with fewer than 10% living longer than two years.

Typically, radiation treatment halts DIPG tumor growth and improves neurologic symptoms temporarily. Chemotherapy drugs don’t reliably work. And surgery isn’t an option on the brainstem, which controls vital functions such as breathing, swallowing and heart rate.

“New options are critical because there are simply no curative options,” explains Christopher Tinkle, MD, PhD, of St. Jude Radiation Oncology, who is leading the study with Amar Gajjar, MD, Pediatric Medicine chair.

“It’s an incurable disease that has remained resistant to all forms of therapy,” Tinkle adds. “It really flies in the face of what we proudly present as such dramatic improvements in pediatric cancer survival rates. It’s a desperate situation that really needs innovation and new ways of thinking.”

Hope out of heartbreak

Decades of research at St. Jude and elsewhere have unraveled DIPG’s mysterious biologic underpinnings. Genetic studies showed how the PI3K signaling pathway is commonly altered in children with DIPG and similar brain tumors. Suzanne Baker, PhD, director of the St. Jude Brain Tumor Research Division, and her colleagues recently discovered that a single mutation in a gene previously not linked to cancer changes the expression of other genes to drive DIPG’s development. The researchers zeroed in on this key mutation, which occurs in most cases of DIPG.

These discoveries were possible through the generosity of St. Jude families affected by DIPG. Many parents of affected children agreed to donate tumor tissue upon their children’s deaths — wrenching gifts fueling hope against a monster disease.

“For decades, these tumors really had remained a black box,” Tinkle says. “But to make progress, we needed insight on a molecular level of the mutations that drive this tumor and what cells they originate from. These kinds of studies can’t be done unless we study the tumor itself, so this was a way to think outside the box.”

Christopher Tinkle, MD, with patient Jessica

The path to progress:
Christopher Tinkle, MD, PhD, shown with St. Jude patient Jessica Waltrip, says he hopes the SJPI3K clinical trial will be the first step in a path toward DIPG treatment gains. As with many other cancers, a strategic blend of therapies will probably be required to improve survival rates.

First steps

The new St. Jude clinical trial is testing a drug known as GDC-0084. Scientists want to find out how well it is tolerated in children and the effects it may have on DIPG and related brain tumors. Like Santiago, patients will first undergo radiation therapy and then take GDC-0084 capsules daily. The drug does what most chemotherapies can’t. It crosses the blood-brain barrier — a natural barrier to keep toxins out — to enable high drug exposure at the tumor site.

Lab studies have shown that GDC-0084 selectively targets the PI3K pathway in glioma cells. By finding its way to the tumor cells and inhibiting this critical growth pathway, the targeted therapy may act as a double-whammy to DIPG cells, preventing cell growth and promoting cell death. In adults who have experienced disease progression with a similar brain tumor, the chemotherapy has been well tolerated. The drug has prevented further tumor growth in several of those patients.

Tinkle describes the clinical trial of GDC-0084 as a “very tough, but necessary first step” on what is likely a long path toward DIPG treatment gains. As with many other cancers, a strategic blend of therapies will probably be required to improve survival rates.

“This is unlikely to be a disease that any one intervention will significantly impact,” Tinkle says. “The direction we’ll be moving is coming up with combinations that cripple the ability of a tumor cell to continue its growth and/or prevent its death.”

I’m gonna dance

Santiago is back to his energetic self after treatment paired with physical and occupational therapy. His tumor appears stable. Feeling more confident and independent again, he spends much of his time perfecting dance moves. Today, he sways to one of his mom’s favorite songs,“Vivir mi vida.”

“I’m gonna laugh; I’m gonna dance. Live, always keep moving forward,” Marc Anthony sings, as Santiago weaves and twirls, displaying elaborate footwork.

Santiago’s optimism and joy of life rub off on everyone around him.

“We’re all fighting, we’re all seeing wins, and we make sure we find ways to win every day,” Eric says. “In these walls, it feels like they only care about the children and a cure. Without question, this is my heaven.”

 

 

The drug used in the SJPI3K clinical trial does what most chemotherapies can’t. It crosses the blood-brain barrier — a natural barrier to keep toxins out — to deliver its potent effects straight to malignant cells.

 

 
 

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