Glioblastoma's secret weapon: Silencing the brain's off switch

HOUSTON -- (Oct. 27, 2026) -- Researchers at Texas Children’s and Baylor College of Medicine have discovered a new strategy that glioblastoma, the most common and aggressive form of adult brain cancer, uses to fuel its own growth. Published in the journal Neuron, the study shows in animal models that glioblastoma hijacks the activity of neighboring brain cells, flipping them from a role that limits tumor growth to one that promotes it. The findings point to new treatment possibilities for this deadly cancer, which has seen only minimal gains in patient survival over the past half century.

"Previous studies from our lab and others showed that glioblastoma and surrounding neurons communicate with each other, and that this conversation makes brain circuits hyperactive, which helps tumors grow faster," said co-corresponding author Dr. Benjamin Deneen, member of the Duncan Neurological Research Institute (Duncan NRI). Deneen is also professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery, Center for Cell and Gene Therapy, and director of the Center for Cancer Neuroscience, all at Baylor. "In the current study, we found a different way glioblastoma manipulates its surrounding environment to favor its own growth."

"We knew that tumors surrounded by hyperactive brain circuits grow faster than tumors surrounded by quieter brain activity. We also knew that two different types of neurons control how active or quiet those circuits are: excitatory neurons send signals that rev up brain circuits, while inhibitory neurons send signals that calm them down," said corresponding author Malcolm F. McDonald, a student in Baylor's Medical Scientist Training M.D./Ph.D. Program and an M.D./Ph.D. Scholar at the McNair Medical Institute at the Robert and Janice McNair Foundation.

To find new ways glioblastoma might trigger this hyperactivity, the researchers screened a panel of epilepsy genes mutated in glioblastoma, removing one at a time to see whether it changed tumor growth. One gene stood out: it codes for a protein called GAT-1, which normally acts like a vacuum, pulling the chemical messenger GABA out of the space between brain cells. GABA is one of many neurotransmitters – chemical messengers – neurons use to communicate with each other, and it is the main signal inhibitory neurons use to calm brain activity.

"We found that removing GAT-1 from tumors accelerated their growth," McDonald said. "That gave us an important clue, and it pointed us toward studying the neurons that keep the brain quiet — a side of this biology that hadn't been examined closely before."

Most prior research on the relationship between glioblastoma and the brain has focused on what drives the neuronal hyperactivity that causes seizures, which affect nearly half of glioblastoma patients.

In the current study, the researchers used animal models and lab techniques that let them switch specific neurons around the tumors on or off. "Activating inhibitory neurons near the tumor reduced tumor growth, compared to that in mice that didn't receive that activation," McDonald said. "And when we blocked inhibitory neurons from calming the surrounding circuits, tumors grew even more, which fits with the idea that this excitatory activity is what's driving tumor growth."

The team also found that glioblastoma produces large amounts of a protein called DBI, short for diazepam binding inhibitor, which ramps up brain circuit hyperactivity and tumor growth. "Importantly, we showed that activating inhibitory neurons next to the tumor can counteract the signals, like DBI, that the tumor sends out to trigger hyperactivity," McDonald said. "There's a ‘push-pull’ between the tumor and the surrounding brain cells, and that gives us a potential therapeutic strategy: stabilizing inhibitory circuits around the tumor to suppress glioma growth."

Building on this, the team tested whether two FDA-approved anti-epileptic drugs that boost GABA signaling, lorazepam (LZM) and valproic acid (VPA), could slow tumor growth. "Both LZM and VPA significantly decreased tumor proliferation compared with mice that didn't receive the anti-epileptics," McDonald said. "That supports pursuing studies into whether these anti-epileptic medications, which already enhance GABA signaling and reduce seizures, also could suppress glioma progression in patients."

"One of the most exciting parts of this research is how it changes the way we think about brain tumors. We traditionally think of tumors as abnormal cells that grow and invade the surrounding brain. What we're learning is that these tumors can also manipulate the activity of nearby brain cells to create the conditions that help them grow. Our study identifies a mechanism by which brain tumors interfere with the brain's natural ability to regulate its own electrical activity, which may contribute to both seizures and tumor progression," said co-corresponding author Dr. Ganesh Rao, Marc J. Shapiro Professor and Chair of Neurosurgery at Baylor. "Importantly, these findings open the door to an entirely new way of thinking about treatment — not just targeting the tumor cells themselves, but also the signals between the tumor and the surrounding brain that let it thrive."

"Seizures are the presenting symptom in nearly half of glioblastoma patients, which highlights how important altered neuronal excitability is in the environment surrounding these tumors," said co-author Dr. Jeffrey Noebels, Cullen Trust for Health Care Endowed Chair in Neurogenetics and professor of neurology, neuroscience and molecular and human genetics at Baylor. Noebels also is the director of the Blue Bird Circle Developmental Neurogenetics Laboratory at Baylor. "The involvement of two druggable regulators of GABA signaling, GAT-1 and DBI, provides compelling evidence that glioblastoma cells co-opt not only excitatory but also inhibitory neurotransmission pathways to promote malignant progression. These findings suggest that restoring GABA-mediated inhibition may offer a novel therapeutic strategy by targeting neuron-tumor crosstalk rather than the tumor alone. I hope clinical trialists in cancer neuroscience take this target-rich microenvironment into consideration, and that future research uncovers new ways to slow the progression of this devastating disease."

"It seems the brain has its own strategies in place for keeping the area around a tumor quiet," Deneen said. "The problem is that as the tumor progresses, it shuts down some of those mechanisms by killing off some of the neurons responsible for them. As a result, the brain loses its ability to keep the tumor's microenvironment quiet, which creates massive excitation — leading to glioma-related seizures and more aggressive tumor progression. We hope our findings lead to new ways to fight glioblastoma and improve outcomes for patients with this deadly disease."

Other contributors to this work include Yeunjung Ko, Rachel N. Curry, Junsung Woo, Roger Ho, Peihao He, Ashley Puentes, Yuhui Yang, Khatri Latha, Eric A. Goethe, Spencer Lea, Gain Seo, Yufei Deng, YeEun Kim, Rajan Patel, A. Basit Khan, Kwanha Yu, Hsiang-Chih Lu and Akdes Serin-Harmanci, all at Baylor College of Medicine.

This work was supported by grants from the NIH (R35NS132230, R01CA284455, R01NS124093, U01CA281902 and R01CA120813). The Baylor College of Medicine Single Cell Genomics Core is supported by NIH Shared Instrument grants (S10OD023469 and S10OD025240), P30EY002520 and CPRIT grant RP200504. The Baylor College of Medicine Pathology and Histology Core is supported by NCI-CA125124.

About Texas Children’s 
Texas Children's, a nonprofit health care organization, is committed to creating a healthier future for children and women throughout the global community by leading in patient care, education and research. Consistently ranked as the best children's hospital in Texas and among the top in the nation, Texas Children's has garnered widespread recognition for its expertise and breakthroughs in pediatric and women's health. The system includes the Texas Children's Duncan NRI; the Feigin Tower for pediatric research; Texas Children's Pavilion for Women, a comprehensive obstetrics/gynecology facility focusing on high-risk births; Texas Children's Hospital West Campus, a community hospital in suburban West Houston; Texas Children's Hospital The Woodlands, the first hospital devoted to children's care for communities north of Houston and Texas Children's Hospital North Austin, the new state-of-the-art facility providing world-class pediatric and maternal care to Austin families. The organization also created Texas Children's Health Plan, the nation's first HMO focused on children; Texas Children's Pediatrics, the largest pediatric primary care network in the country; Texas Children's Urgent Care clinics that specialize in after-hours care tailored specifically for children; and a global health program that is channeling care to children and women all over the world. Texas Children's Hospital is affiliated with Baylor College of Medicine. For more information, visit www.texaschildrens.org.