Beyond Radiation: The Research Seeking a Future for Children with DIPG

For children diagnosed with diffuse intrinsic pontine glioma (DIPG) (搜索)搜索该疾病, 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 (搜索)搜索该词条 is currently funding 13 research projects involving diffuse midline glioma (DMG) (搜索)搜索该疾病, the broader category that includes DIPG, according to a grant list the organization provided to The Citizen. Some focus specifically on DMG, while others study approaches that could apply to several pediatric brain tumors or other childhood cancers. "We are philanthropic seed investors in the next great discovery," said Dean Crowe, founder and chief executive officer of Rally. "Our main thing, our main focus, is the research."

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查看公司主页, said radiation remains the only established therapy that consistently benefits children with the disease.

"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, but 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查看公司主页, which he described as the hospital's early-phase oncology clinical-trials program—work focused on developing and testing new drugs and treatment techniques.

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查看药品详情, which begins with a patient's own immune cells. Those cells are collected and modified so they can recognize a particular target on cancer cells, then returned to the patient to seek out and attack those cells.

The approach has produced major advances in some blood cancers, but its role in DIPG remains experimental. Fangusaro said CAR T-cell therapy查看药品详情 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, but 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 these challenges, studying ways to restore exhausted CAR T cells, identify better targets on pediatric brain tumors, and improve the signals that activate immune cells.

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, and 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 (搜索)搜索该靶点, which 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, as well as research into which type of developing brain cell first gives rise to a pediatric high-grade glioma.

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—but 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. 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. Each approach remains under investigation, and 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. Another project is studying the microbiome and its possible role in pediatric central nervous system tumors.

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, and 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 (搜索)搜索该词条 after learning how little funding was available for childhood-cancer research. The foundation's seed-investment model is designed for projects that may be too early to compete successfully for large federal grants. Crowe said Rally has awarded $47.5 million in research grants across the United States and internationally, and that 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.

Not every grant will produce a treatment. Some projects will show that an approach does not work, while others may reveal a piece of tumor biology that becomes useful years later or in combination with discoveries from another laboratory. 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.

"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, but 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.

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.

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, and 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—but for researchers and funders, they are the starting points for trying to change what the next family hears.