After decades with no new therapies, pivotal new research into the brain tumor DIPG fuels possibilities for more effective options.

The moment has long been seared into Darrel Adkins’ memory: Arriving at St. Jude Children’s Research Hospital with his daughter, Mandy, the frightened father thrust his hand forward to greet the check-in nurse. But his handshake was rebuffed in the best possible way.

“The nurse told me, ‘We hug here. We’re family,’” Darrel recalls. “And that’s what we were.”

The family feeling embodied at St. Jude has never left Mandy’s parents in the years since their vibrant daughter died of a rare brainstem tumor called glioblastoma in November 2000. Darrel and Phyllis Adkins dedicated an annual music festival in their home state of Ohio to Mandy’s memory. Almost all of the nearly $1 million they’ve raised from the event thus far has been donated to brain tumor research at St. Jude.

Such great intentions have now begun to pay off in pivotal ways. St. Jude researchers are beginning to untangle the deepest secrets of devastating brain tumors — which confounded scientists for decades — offering new hope for effective treatments.

 “Our money is seed money, that’s what we call it,” says Darrel, who regularly travels with Phyllis to St. Jude to glimpse the technology and talent their donations help fund. “People still ask what it’s going to take to find the cure for cancer. After seeing what goes on at St. Jude, my answer is ‘money.’ Money pays for research. I’m so glad we did this.”

A scientist’s greatest hope

Building on years of dogged discovery, Suzanne Baker, PhD, director of the hospital’s Brain Tumor Research Division, recently led a team that generated a lab model for another brain malignancy known as diffuse intrinsic pontine glioma (DIPG). Baker and her colleagues discovered how one gene mutation changes the expression of other genes in this lethal brainstem tumor’s development.

“My greatest hope is that our research would show us how to stop this terrible disease,” she says.

Although Baker has spent most of her lab career focusing on DIPG and other deadly high-grade gliomas, the human toll of brain tumors has never escaped her.

As a doctoral student in the 1980s, she attended a bluegrass festival organized by Darrel and Phyllis Adkins. Baker vividly remembers spotting a dancing Mandy Adkins onstage, a little girl lost in the music.

“It was a really surprising connection — much more than a researcher typically would have to a patient’s family,” says Baker, who now meets with the couple every time they visit St. Jude and has spoken at their annual festival, Musicians Against Childhood Cancer.

Challenges to effective treatment

Baker’s new studies, published in the journals Cancer Cell and Acta Neuropathologica, provide potential pathways to accomplish her goal of eradicating DIPG. Diagnosed in several hundred children each year in the United States, DIPG comes with an especially grim prognosis: Young patients survive only nine months on average, with fewer than 10% living longer than two years after diagnosis.

But surgery isn’t a treatment option because the brainstem, which controls vital functions such as breathing, swallowing and heart rate, can’t be removed. And while radiation and chemotherapy can help extend the lives of DIPG patients, the disease is exceptionally resistant to these therapies. More-effective options haven’t emerged in the last 50 years.

“The tumors do respond initially to radiation, but then they recur. And in children, there’s still not a standard of care for chemotherapy because there’s not clear proof that any chemotherapy consistently extends survival in childhood high-grade glioma whether it’s in the brainstem or not,” Baker explains.

“Part of the problem is that our brains have a natural barrier to keep toxins out. We call it the blood-brain barrier, and it actually does a good job keeping a lot of drugs out of the brain,” she adds. “So if we find a drug we think is promising, but it doesn’t get to the tumor, it’s not going to help. It’s a challenging situation.”

Discovery of key mutation

In 2012, Baker and St. Jude colleagues in seven departments revealed a web of related genetic alterations essential to understanding how DIPG develops. While many types of cancer arise from gene mutations that drive uncontrolled cell growth, mutations influencing DIPG stem from deviations in the cell’s so-called epigenetic machinery, which oversees how genes are turned on or expressed.

The researchers pinpointed a key mutation called H3 K27M that occurs in most cases of DIPG. This mutation arises in a gene that codes for histones. Histones are molecules that help to package the DNA in cells. Chemical changes in the histone proteins can influence whether genes are activated or kept inactive.

“There had never been a histone mutation identified in human cancer before,” Baker explains. “It really tells you that this is something that’s very, very important for this disease.”

Because histones are crucial to every cell of the body, Baker wondered why the H3 K27M mutation showed up so often in brain gliomas. To solve the mystery, the St. Jude researchers used genetic engineering to create a lab model that selectively switched on the mutation in the same type of brain cell that gives rise to DIPG in children.

The project unveiled critical ways the mutation causes DIPG. For instance, the mutation triggers immature cells known as stem cells from the developing brainstem to multiply abnormally, but only during a narrow window of development. This short-lived effect on stem cells may help explain why most DIPGs develop in early childhood.

“We thought it would be important to try to model this as accurately as we could because the actual tumors are already telling us that the K27M mutation is really only playing a critical role in a very specific developmental context,” Baker says.

Brakes and accelerators

Baker and her colleagues also learned that the H3 K27M mutation works together with a pair of other gene mutations that are known to drive DIPG tumors. One mutation removes a “brake” on cell growth, while the other sparks a cell growth “accelerator” to work overtime. Adding the histone mutation accelerated the speed of brain tumor formation and caused most of the tumors to form in the brainstem. The lab-generated tumors closely resemble those from children with DIPG — making this the most accurate effort yet to portray DIPG in lab conditions.

 “Now we have a much cleaner comparison, where it’s easier to see what the contribution of the histone mutation is without all of that variation you typically get from one person to another,” Baker says.

In a different model system, the researchers turned off the H3 K27M mutation and showed that it slowed tumor growth and made some of the tumor cells develop into more mature cell types that stop multiplying. In both model systems, the researchers showed that the histone mutation turned on a collection of genes related to brain development — likely contributing to DIPG growth by keeping tumor cells in a more primitive state when they continue to multiply.

The new revelations were built on years of research by Baker and others to identify gene mutations involved in high-grade gliomas, which account for up to one in five brain and spinal tumors in children. Through advances in genomics made possible in the early 2000s, scientists identified genetic missteps driving the tumors.

A highly publicized St. Jude collaboration with the Washington University Pediatric Cancer Genome Project in 2014 linked recurring mutations in the ACVR1 gene to a third of DIPG patients. That research also revealed an alteration in NTRK genes driving tumor development in young high-grade glioma patients whose tumors developed outside the brainstem.

A new era of discovery

Baker’s research over the past decade would never have been possible without the generosity of St. Jude families affected by DIPG. She worked with a clinical colleague who devised a protocol that allows parents of an affected child to donate tumor tissue upon the child’s death.

While the request proved excruciating, “a number of families actually reported that this was important to them—that it was something that gave some meaning to what they had gone through,” she says. “Without the tissue donations, we really would have had no way to look at the disease.”

Now Baker’s new lab model of DIPG will enable scientists to take the next step: testing new therapies for the malignancy, and even boosting understanding of other tumors triggered by such mutations. The connection between epigenetics and childhood brainstem tumors has also drawn the attention of researchers worldwide, she notes, expanding the number who devote their efforts toward the field.

“For us to be more effective with therapy for these tumors, we really have to understand what is going wrong, what caused the problem to start with,” Baker says.

“This is a long game,” she acknowledges, “but the last few years of basic research have completely changed the way we view DIPG. We understand things we never imagined before in terms of the mutations that drive this disease.”