Existing anti-seizure drug slows the growth of diffuse midline gliomas

An existing anti-seizure drug slows the growth of a devastating group of childhood cancers, new Stanford Medicine-led research has shown. The tumors, called diffuse midline gliomas, strike the brain and spinal cord. They affect 300 to 400 U.S. children per year and have a five-year survival rate of about 1%.

The study, which will publish Sept. 17 in Nature Medicine, showed that a medication called levetiracetam slows the tumors' growth by unplugging their electrical connections to healthy neurons.

In addition, data from medical records of diffuse midline glioma patients who received levetiracetam showed that they lived longer, on average, than those who did not. The researchers are now planning clinical trials to further test how well the drug works.

"This is very exciting for a disease that has had so few treatment options," said senior author Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology and professor of neurology at Stanford Medicine.

The study's lead author is Tara Barron, PhD, who was a postdoctoral scholar at Stanford Medicine when the work was performed and is now an assistant professor of pathology at the University of Texas Southwestern Medical Center.

The finding is one fruit of a new field called cancer neuroscience, which Monje pioneered to study how malignant cells connect to and hijack signals from the healthy nervous system to fuel their own growth.

"This drug pharmacologically severs an important connection between cancer and the nervous system," Monje said. An especially promising part of the new findings was the discovery that levetiracetam acts through a different mechanism in cancer cells than in healthy cells, she added, increasing the chance that the drug can attack the cancer without disrupting healthy cell function.

Tumors that take advantage of normal brain signals

Diffuse midline gliomas use signals from healthy brain cells that reach them via cell-to-cell electrical connections called synapses to fuel their malignant growth, prior Stanford Medicine research found. One synapse type that powerfully drives the growth of diffuse midline gliomas are GABAergic synapses. The discovery was made in diffuse intrinsic pontine glioma, aka DIPG, a deadly type of midline glioma that grows in the brain stem.

Brain tumors tend to cause seizures, so some patients receive anti-seizure drugs. Levetiracetam, also known by the brand name Keppra, reduces excess excitatory signaling between healthy neurons. It is often given to brain tumor patients experiencing seizures or to prevent seizures because it has few side effects and does not interact with other medications.

Some previous studies suggested that brain tumor patients who received levetiracetam might live longer than those not taking the drug, but results were mixed. To explore the idea, Monje's team used medical record data from 218 pediatric brain tumor patients who had been treated at two academic medical centers. All patients had high-grade gliomas, aggressive tumors originating from the central nervous system's glial cells, but not all tumors originated in the same locations.

When the data was analyzed based on the type and location of the tumors, the scientists found that levetiracetam was linked to longer survival in patients with diffuse midline gliomas - high-grade gliomas that originate in the brain stem, thalamus or spinal cord. But patients with hemispheric high-grade gliomas, which began in other parts of the brain, did not survive longer when taking the drug. The researchers decided to further study how the drug behaves in these two kinds of tumors.

Different tumors, different results

The researchers followed up with a series of experiments in animal models. In mice with diffuse midline gliomas grafted from human patients, levetiracetam slowed the growth of the malignant cells. However, in mice with hemispheric high-grade gliomas like glioblastoma, the drug did not slow the tumors' growth.

The researchers demonstrated that levetiracetam blocked electrical signals from nearby neurons to the diffuse midline glioma cells through GABAergic synapses. This was surprising, because levetiracetam does not affect GABAergic synapses in healthy neurons. Hemispheric high-grade gliomas, which the team previously found did not have the same type of GABAergic synapse, also were not affected by levetiracetam.

Interestingly, the medication does not operate in diffuse midline gliomas via the molecular mechanism that quells seizures in noncancerous brain cells, the researchers showed. The exact pathway of the tumors' response to levetiracetam in the tumors is still unknown; Monje's team is continuing to investigate it.

"What's really interesting is that this is tumor-specific," Monje said. The unique activity in tumors holds promise for attacking cancer without disrupting healthy neurons, she said. Her team is launching a clinical trial of levetiracetam for patients with the tumors.

Although hemispheric high-grade gliomas do not respond to levetiracetam, other research from Monje's team has shown that the drug reduces growth of certain tumors that start in other parts of the body and metastasize into the brain. A paper published last year found that levetiracetam slows the growth of small cell lung cancer that has spread to the brain; the researchers are now investigating whether it works on other cancers that move into the brain. The work has potential to unlock new treatments for a phase of cancer's spread that has been very difficult to treat.

"It's incredibly important to study these childhood cancers that take the lives of hundreds of kids, just in the U.S., every year," Monje said. "Not only for their sake, but also because what we learn in these relatively rare childhood brain cancers can inform our knowledge of much more prevalent adult cancers."

Although levetiracetam alone is unlikely to cure aggressive brain tumors, Monje believes it could be a helpful tool to combine with other forms of cancer therapy. In a clinical trial of children with diffuse intrinsic pontine glioma and other diffuse midline gliomas, her lab is studying CAR-T cells, immune cells engineered to attack the brain tumors, a strategy that is showing promise.

"You can think of immunotherapy as a footrace between the tumor and the immune cells," she said. "We want the immune cells to get ahead of the tumor. Our new data shows that levetiracetam slows the tumor down."

The research is also a great example of how knowledge of cancer neurobiology enables researchers to test existing neurological and neuropsychiatric drugs against tumors, she said.

"These repurposed neurologic drugs hit the very mechanisms the cancers are hijacking," she said. "That makes for a very important and promising area of therapy, with a low bar to implement, because we already know the drugs' safety profiles and they're already designed to get into the brain."

Researchers contributed to the study from the University of Michigan; the University of California, San Francisco; the University Medical Center Hamburg-Eppendorf; and the University of Helsinki.

The research was funded by grants from ChadTough Defeat DIPG Foundation, the National Institute of Neurological Disorders and Stroke (grant R01NS092597), a National Institutes of Health Director's Pioneer Award (DP1NS111132), the National Cancer Institute (P50CA165962, R01CA258384 and U19CA264504), the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, Cancer Research UK and Cancer Grand Challenges, the Gatsby Charitable Foundation, Oscar's Kids Foundation, the McKenna Claire Foundation, the Kyle O'Connell Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the Waxman Family Research Fund, the Avery Huffman DIPG Foundation, the Will Irwin Research Fund of the Pediatric Cancer Research Foundation, The William E. and Carolyn Reller Oligodendroglioma Research Fund, the Jacob Van de Roovaart Glioblastoma Research Fund, the Milan Gambhir Professorship in Pediatric Neuro-Oncology, the Chambers-Okamura Endowed Directorship for Pediatric Neuro-Immuno-Oncology, the Botha-Chan Family Research Fund, the Myers Family Fund, the Cancer Prevention and Research Institute of Texas, Alex's Lemonade Stand Foundation, the Weekly Family Research Fund, the Timon Labintcev Pediatric Brain Tumor Award, the Yuvaan Tiwari Foundation, and the Enzo & Me Pediatric Cancer Foundation.