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In the first installment of DIPG Close to Home, The Citizen told the story of Rosalie, who was given nine months to live after her diagnosis and died nearly two years later at age 8. Part 2 followed 6-year-old Aubrey Ward, a Peachtree City child who completed radiation and is pursuing an experimental CAR T-cell treatment.
Their stories show the devastating reality of diffuse intrinsic pontine glioma, or DIPG—a type of diffuse midline glioma, commonly called DMG. This final installment looks at the researchers and funders working to give children like Rosalie and Aubrey better options than families have today.
For a child diagnosed with DIPG, radiation can sometimes restore movement, improve swallowing and shrink the tumor enough to provide months of more normal life.
Then, in most cases, the tumor begins growing again.
That is the problem researchers across the United States and abroad are trying to solve—by reprogramming immune cells, studying the machinery inside the tumor, finding new ways to deliver treatment into the brain and developing better methods of monitoring the disease.
Rally Foundation for Childhood Cancer Research is currently funding 13 research projects involving DMG, according to a grant list the organization provided to The Citizen. Some focus specifically on DMG. Others study approaches that could apply to several pediatric brain tumors or other childhood cancers.
Together, they show researchers attacking the disease from many directions.
“We are philanthropic seed investors in the next great discovery,” said Dean Crowe, founder and chief executive officer of Rally.
The foundation’s goal, she said, is to support promising ideas early, help researchers produce evidence and position successful projects to attract larger investments from federal agencies and other funders.
“Our main thing, our main focus, is the research,” Crowe said.
A disease that still has no reliable cure
DIPG develops in the pons, a part of the brainstem involved in breathing, swallowing, heart rate, balance and movement.
Its location makes surgical removal impossible without destroying essential neurological functions.
Dr. Jason Fangusaro, a pediatric neuro-oncologist at Children’s Healthcare of Atlanta, said radiation remains the only established therapy that consistently benefits children with the disease.
It can improve symptoms and shrink the tumor. But the improvement is usually temporary.
“Although this typically decreases some of the symptoms they have and causes the tumor to shrink, in most cases, within six to eight months, sometimes sooner, the tumor will start to grow again,” Fangusaro said.
A second course of radiation can sometimes provide another period of improved function and quality of life. It still does not cure the cancer.
That leaves families searching for clinical trials and researchers searching for treatments that work differently from radiation.
Fangusaro leads the developmental therapeutics program at Children’s Healthcare of Atlanta. He described it as the hospital’s early-phase oncology clinical-trials program—work focused on developing and testing new drugs and treatment techniques.
Rally referred The Citizen to Fangusaro for this series and has funded his research in the past, according to the foundation. He is not listed among the investigators receiving one of Rally’s current DMG grants.
His experience helps explain the distance between an idea in a laboratory and a treatment available to a child.
A project may begin by identifying something unusual about a tumor cell or testing an approach in a laboratory model. Researchers must then study safety, determine whether a treatment can reach the tumor and learn whether it has enough potential to justify testing in patients.
Even when a treatment reaches a clinical trial, researchers still must determine whether it is safe and whether it actually helps children live longer or better.
Training immune cells to attack the tumor
Several projects on Rally’s current list involve immunotherapy—using or modifying the body’s immune system to recognize and attack cancer.
Among the most closely watched approaches is CAR T-cell therapy.
CAR T-cell treatment begins with a patient’s own immune cells. Those cells are collected and modified so they can recognize a particular target on cancer cells. They are then returned to the patient to seek out and attack those cells.
The approach has produced major advances in some blood cancers. Its role in DIPG remains experimental.
Fangusaro said CAR T-cell therapy has drawn more attention than other recent DIPG treatments because some early studies have shown tumors shrinking without radiation.
“The only other therapy that recently has gotten attention—and we can’t say that it’s effective yet, but it seems more promising than anything else has been for over 50 years—is something called CAR T-cell therapy,” he said.
A small number of patients have experienced longer survival, Fangusaro said. Most children in the early studies have still ultimately died from the disease.
The challenge is not simply creating an immune cell capable of attacking cancer. Researchers also must help those cells reach the tumor, remain active and continue functioning in an environment that can weaken the immune response.
Several Rally-funded projects address those challenges. Researchers are studying ways to restore exhausted CAR T cells, identify better targets on pediatric brain tumors and improve the signals that activate immune cells.
Other projects examine whether changes in the tumor’s genetic controls could make DMG more responsive to immunotherapy.
The studies differ in their methods, but they address versions of the same question: How can researchers help the immune system recognize this tumor, reach it and continue fighting it?
Understanding what makes the tumor grow
Other Rally-supported researchers are studying what happens inside the tumor cells themselves.
Over approximately the past decade, biopsies have allowed doctors and researchers to learn more about the molecular characteristics of DIPG.
In earlier years, physicians often diagnosed the disease from its distinctive appearance on an MRI. Biopsies were avoided because of the sensitivity of the brainstem.
Fangusaro said biopsies are now performed more frequently and can be done safely at experienced centers. The tissue does not usually change the child’s prognosis, but it gives researchers information about the tumor and may allow the child to be eligible for a specific, novel clinical trial.
“What we’ve learned is that this tumor, far and away, has a very unique molecular characteristic,” he said.
One important alteration is known as H3K27M. It affects how genetic instructions are regulated inside tumor cells and helps define many diffuse midline gliomas.
Researchers hope that understanding those changes will expose weaknesses that can be targeted with treatment.
Projects on Rally’s current list include studies of the epigenetic processes that control whether genes are turned on or off. When those controls malfunction, cells may grow or behave abnormally.
Other researchers are studying which type of developing brain cell first gives rise to a pediatric high-grade glioma and whether that process can be interrupted.
These grants do not mean researchers have identified one switch that can simply be turned off to stop DIPG. They represent efforts to understand the disease closely enough to find a treatment target that is both effective and safe.
Reaching a tumor protected inside the brain
Even an effective cancer drug cannot work if it cannot reach the tumor.
The brain is protected by the blood-brain barrier, a network that helps prevent harmful substances from entering brain tissue. That protection can also prevent cancer treatments from reaching their target in sufficient amounts.
The location of DIPG creates another challenge. Researchers must reach a tumor woven through a part of the brain that controls functions necessary for life without seriously damaging healthy tissue.
Several Rally-funded projects examine ways to overcome those barriers.
One project at Georgia Tech Research Corporation is studying whether precisely directed electrical pulses can be used to target tumor tissue and temporarily disrupt the blood-brain barrier.
Another, at the University of Florida, is examining focused ultrasound as a way to deliver personalized nanoparticle vaccines to brain tumors.
Focused ultrasound uses concentrated sound energy directed at a precise location. Researchers are investigating whether it can help treatments cross into the brain while limiting effects on surrounding tissue.
A project at the University of Texas MD Anderson Cancer Center is studying a treatment that combines inhibition of a tumor-related protein with an oncolytic virus.
Oncolytic viruses are altered or selected to infect and damage cancer cells while potentially stimulating an immune response against the tumor.
Each approach remains under investigation. The grant list does not indicate that any has been proven effective in children with DIPG.
Improving radiation and monitoring the disease
Because radiation remains the most consistently useful treatment available, researchers are also studying whether it can be delivered or combined with other approaches more effectively.
One Rally-supported project examines how the rate at which radiation is delivered affects epigenetic and immune responses in DMG.
The question matters because radiation does more than damage tumor cells. It may also alter the tumor environment and affect how immune cells respond. Understanding those effects could help researchers design better treatment combinations.
Another project is studying the microbiome—the collection of microorganisms that live in and on the body—and its possible role in pediatric central nervous system tumors.
Researchers increasingly study how the microbiome interacts with immune function, disease and treatment response. Rally’s grant list does not describe what role the researchers have found, or expect to find, in DMG.
A project at Children’s Hospital Los Angeles is developing a comprehensive liquid-biopsy assay for pediatric cancer.
A liquid biopsy looks for tumor-related material in blood or another body fluid. If successful, such tools may eventually help doctors monitor how a tumor responds to treatment without repeatedly obtaining tissue.
The grant list does not state whether the assay has reached clinical use or exactly how it would be used in children with DIPG.
Funding the first steps
Crowe founded Rally Foundation for Childhood Cancer Research after learning how little funding was available for childhood-cancer research.
The organization raises money for work intended to produce better treatments, fewer long-term side effects and, ultimately, cures. It also helps families with needs including travel, meals and some household expenses.
Crowe said the research remains Rally’s central focus.
The foundation’s seed-investment model is designed for projects that may be too early to compete successfully for large federal grants.
A researcher may have a strong scientific idea but still need initial data demonstrating that the idea deserves further investment. Philanthropic funding can provide money for those early experiments.
Crowe said Rally has awarded $47.5 million in research grants across the United States and internationally. She said those early investments have helped researchers generate the evidence needed to attract more than $1 billion in additional support from federal agencies and other organizations.
Rally’s role, she said, is often to provide the first funding behind a promising idea—before the project is developed enough to compete for much larger grants.
The foundation may continue supporting work that shows promise, Crowe said, with the goal of helping it progress toward larger funding and clinical trials.
Not every grant will produce a treatment. Some projects will show that an approach does not work. Others may reveal a piece of tumor biology that becomes useful years later or in combination with discoveries from another laboratory.
That uncertainty is part of early research.
But for a disease with no reliable cure, Crowe said researchers must be able to test new ideas.
“Clinical trials for these kids are critical because they help to try out new therapies,” she said.
Connecting families with trials
Research only becomes relevant to an individual child when a family and medical team can find an appropriate trial—and when that child qualifies to participate.
Fangusaro serves on the Diffuse Midline Glioma National Tumor Board, a group of specialists who review cases submitted from across the country.
The board meets every two weeks, he said, and provides families and physicians with information about clinical trials for which a child may be eligible.
A family might learn that a trial is available at Children’s Healthcare of Atlanta, Stanford, Seattle Children’s, Baylor or another institution.
The resource is intended to help families navigate a field that can become overwhelming immediately after diagnosis.
“For a family to feel like they have to navigate that alone is very difficult,” Fangusaro said.
The board cannot promise that a trial will work. It can help families understand what options exist and where they are available.
Fangusaro also encouraged families to be empowered to ask their provider about a second opinion or about having their child’s case presented to the National DMG Board if this is something important to them.
Promise without a promise
The 13 active projects on Rally’s list do not represent 13 treatments ready for children.
They include laboratory studies, treatment-development projects and work that may apply to several forms of childhood cancer. The list does not provide research results or establish that any of the approaches will ultimately succeed.
What it shows is the range of questions researchers are pursuing:
Can immune cells be engineered to recognize the tumor and remain strong enough to fight it?
Can scientists exploit the molecular changes that make DIPG different from healthy brain tissue?
Can treatment cross the blood-brain barrier and reach the tumor safely?
Can radiation be used in a way that improves the immune response?
Can doctors monitor the disease through a blood sample rather than relying only on imaging or tissue?
No source interviewed by The Citizen described an existing cure.
Fangusaro was careful not to offer families a promise the evidence cannot yet support.
But he also described a field that is learning more about the tumor than it knew when he began practicing more than 20 years ago.
Biopsies have revealed molecular characteristics. National tumor boards help families locate trials. CAR T-cell studies have produced tumor shrinkage in some children. Researchers are developing methods intended to help treatments reach one of the most protected and sensitive areas of the body.
For children diagnosed today, those advances have not yet changed the fundamental reality of DIPG.
For researchers and funders, they are the starting points for trying to change what the next family hears.
How to help
Readers who would like to support Rally Foundation for Childhood Cancer Research can donate through the “Give Now” option on the foundation’s website. Rally accepts donations to support its work funding childhood-cancer research and assisting families affected by the disease.
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