Diffuse midline glioma (DMG) is an aggressive tumor that grows in the central structures of the brain, including the thalamus, brainstem, and spinal cord. The tumor is characterized by its diffuse nature, as its cells infiltrate healthy brain tissue, making it difficult to surgically remove. It primarily affects children and young adults, with a peak incidence between the ages of 5 and 10.
This tumor is defined by a specific genetic alteration, the H3 K27M mutation. This change is understood to be the primary driver of its growth and aggressive behavior. The discovery of this mutation has changed how these tumors are classified and opened new avenues for targeted treatments.
The Role of the H3 K27M Mutation
Gliomas are tumors originating from glial cells, the supportive cells of the central nervous system. Inside each cell’s nucleus, DNA is wound around proteins called histones. This packaging system helps control which genes are active or silent, a process known as epigenetics. Chemical marks on these histone proteins act as switches, guiding how the genetic code is read.
The defining feature of this glioma is an error in the gene coding for the histone H3 protein. This error, the H3 K27M mutation, involves a single amino acid substitution where a lysine (K) is replaced by a methionine (M) at the 27th position. This small change has profound consequences for the cell’s epigenetic regulation. The lysine at this position is normally a site for methylation, a chemical mark that signals for genes to be turned off.
The methionine in the mutated H3 protein disrupts an enzyme complex called PRC2, which normally adds methyl groups to the K27 position. The mutation inhibits PRC2, leading to a global reduction in this methylation mark across the genome. This loss of a gene-silencing signal causes a cascade of abnormal gene activation.
With normal epigenetic controls broken, genes that promote cell division are switched on, while genes that suppress tumor formation are left inactive. This uncontrolled expression drives the glioma’s growth. Understanding this molecular mechanism was a breakthrough, providing a specific target for developing new therapies aimed at reversing these epigenetic changes.
Symptoms and Diagnosis
Symptoms of a diffuse midline glioma relate directly to the tumor’s location. A tumor in the brainstem, particularly the pons, can interfere with cranial nerves. This leads to symptoms like double vision, difficulty with eye movement, facial weakness, and problems with swallowing or speaking. Balance and coordination issues are also common.
If the tumor is in the spinal cord, symptoms may include progressive weakness in the arms or legs, numbness, or difficulty with bladder and bowel control. A glioma in the thalamus can cause sensory changes on one side of the body, weakness, or cognitive and memory problems.
Diagnosis begins with a neurological exam, followed by magnetic resonance imaging (MRI) of the brain or spine. An MRI provides detailed images that reveal the presence, size, and infiltrative nature of a tumor in a midline location.
While imaging is suggestive, a definitive diagnosis requires confirming the H3 K27M mutation through a surgical biopsy. During a biopsy, a small sample of tumor tissue is removed. Molecular testing on this tissue then identifies the specific genetic signature, which dictates the prognosis and treatment strategy.
Current Treatment Approaches
The standard of care for newly diagnosed diffuse midline glioma is radiation therapy. This treatment uses high-energy X-rays to damage the DNA of cancer cells, slowing their growth. Radiation is a palliative measure that can temporarily shrink the tumor and alleviate symptoms, but it is not curative. The benefits are often temporary, with tumor progression occurring months after treatment.
Surgical removal is not a viable option because these tumors infiltrate sensitive brain structures that control functions like breathing and heartbeat. Attempting to resect the tumor would cause severe neurological damage. The goal of treatment is to control the tumor while maintaining the patient’s quality of life.
Conventional chemotherapy drugs have shown limited effectiveness against these gliomas. A challenge is the blood-brain barrier, a protective membrane that prevents most chemotherapy agents from reaching the tumor. The few drugs that can cross this barrier have not successfully stopped tumor growth, leading researchers to explore other therapies.
Emerging Therapies and Clinical Trials
Understanding the H3 K27M mutation has spurred therapies designed to counteract its effects. One of the most studied is a small molecule inhibitor called ONC201. This drug has been observed in clinical trials to affect the tumor’s metabolism and reverse some epigenetic changes caused by the mutation, improving survival for some patients. Research continues to refine its use and explore combinations with other treatments.
Immunotherapy, which harnesses the body’s immune system to attack cancer cells, is another area of research. Approaches include cancer vaccines that train the immune system to target glioma cells. Another strategy is CAR-T cell therapy, where a patient’s T-cells are genetically engineered to find and destroy cells with the H3 K27M mutation.
A challenge in treating any brain tumor is delivering drugs across the blood-brain barrier. To address this, scientists are investigating novel delivery systems. These include convection-enhanced delivery, which uses a catheter to infuse drugs directly into the tumor, and nanotechnology to package drugs in particles that can cross into the brain.
These advanced treatments are considered experimental and are available to patients through clinical trials. These studies test the safety and effectiveness of new therapeutic strategies. For patients and families, clinical trials offer access to the next generation of potential treatments.