Harald Sontheimer, PhD, is internationally recognized for pioneering the field of cancer neuroscience — a discipline that reframes how scientists and clinicians approach gliomas and other brain tumors. This summer, his groundbreaking work earned him the Gertrud Reemtsma Foundation's 2025 International Prize in Translational Neuroscience.
At UVA Health, Sontheimer serves as a leader in both research and education, bringing together teams that bridge oncology and neuroscience in ways still uncommon at most institutions. His work has illuminated how gliomas hijack ion channels and release glutamate to drive tumor growth and seizures — and how unlikely sources like scorpion venom can inspire novel therapies.
In this conversation, Sontheimer shares insights into the science behind these discoveries, the infrastructure at UVA Health that accelerates translation, and where he sees the most promising paths forward for improving patient care.
You’re widely credited with helping establish cancer neuroscience. How does this perspective shift the way we think about gliomas compared to traditional oncology models?
Our approach to identify how gliomas differ from normal brain cells and how they interact with the brain provides an alternative vantage point that is synergistic to our traditional cancer-focused approach.
The finding that neurotransmitters such as glutamate and ion channels typically used only by neurons are fundamentally important in driving glioma growth and invasion suggests a number of therapeutic strategies we would not have identified had we not taken what I call a “neurocentric” perspective with our research.
Early in your career, you discovered that glioma cells hijack ion channels to infiltrate brain tissue. What implications does this have for how we target tumor invasion?
These studies were indeed among the first to show a role for ion channels in cancer that is now widely recognized. For a number of these channels, there are specific inhibitors available that could be explored in clinical trials, such as we did with chlorotoxin.
There are current therapeutic approaches aimed directly at ion channels and cell volume regulation, albeit most are in early stages. For example, the K+/Cl- cotransporter (KCC2) and the Na+/K+/2Cl- cotransporter (NKCC1) are being explored in clinical studies, as are selective blockers of sodium and potassium channels.
The chlorotoxin work — beginning with scorpion venom and now intersecting with CAR T-cell therapy — is a remarkable translational story. What lessons can we draw from that journey about moving discoveries into the clinic?
Well, the most important lesson, of course, is that basic science that seeks to learn how biology works can yield important insights and new clinical targets. Chlorotoxin may seem like an outlandish discovery. However, just about any ion channel has a highly specific inhibitor in one of many poisonous animals, mostly spiders and scorpions. These evolved to allow a predator to kill or paralyze its prey. That makes ion channels a very opportune target, as these molecules are often highly refined and bind with great specificity and high affinity.
Once a scientist makes a discovery they think is important, they typically run with it and keep pursuing it to the end. In our case, collaboration with medicinal chemists, neurologists, and radiation oncologists was key. You typically find those colleagues only in medical schools; therefore, having researchers at medical schools commingle with clinicians is a perfect recipe for success.
Your lab has also shown that gliomas release glutamate, causing both excitotoxicity and seizures. How should clinicians think about seizures not just as symptoms but as part of the tumor’s biology?
I would argue that seizures are a biomarker not just that something is going wrong in the brain, but, in the case of a glioma, that there is active growth and engagement of glutamate in that growth. It is those patients who are most likely to benefit from glutamate-targeted therapy.
Targeting glutamate release could change the natural history of these tumors. But that alone will not do. I think combining a glutamate-targeted strategy with immunotherapy may be most promising. Monotherapy for cancer is rarely effective.
What role does the Paul and Diane Manning Institute of Biotechnology play in ensuring discoveries like these can be advanced without the usual funding and translation bottlenecks?
Honestly, looking back 30 years, had we had a Manning Institute, there would not have been the need to spend a lot of time and energy to start a biotech company and raise funds to produce the drug and feed it into clinical trials.
The Manning Institute will have medicinal chemistry on site, allowing you to design the therapeutic drug. It also houses a GMP facility where the drug could be produced to clinical standards. And its interactions with Neurology and the Cancer Center would have allowed us to move from the bench to the bedside quickly, cost-effectively, and all right here at UVA.
You’ve built neuroscience programs at several institutions. How does that leadership experience shape the way you approach team science and mentoring at UVA?
Firstly, assume that everyone in your orbit is smarter than you are and can be helpful if asked. I got so much advice from the Cancer Center director and his team as to what needs to be done. I had my best interactions with neurologists and neurosurgeons who best understand the problem and who are as passionate about helping people as we were.
Understand that initially any discovery is just a glimmer in your eye. It takes persistence to convince others that what you are pursuing has value. Have patience and ask for help. Don’t reinvent the wheel. There is often a well-traveled path from discovery to a clinical trial, and you need to find the right people to join and guide you on that journey.
Looking ahead, what areas of glioma biology do you think hold the most promise for near-term therapeutic advances?
I am a strong believer in immunotherapy. The recent advances in myeloid cancers are really inspiring. Particularly, directing CAR T-cell therapy to recognize and eliminate cancers has moved very much into clinical reality.
I do think that neurotransmitter receptor modulators and ion channel blockers hold promise in glioma but need much further work.
Well, obviously, for just about all cancers we would really like to know their origin. How did the first mutation come about that led to the first uncontrolled cell division? After all these years of beautiful cancer cell biology, our true understanding of genetic risk and environmental exposure are still incomplete. The deployment of single-cell and spatial transcriptomics, however, is giving us unprecedented insight into tumor biology that will accelerate closing gaps in our knowledge.
What perspective would you share with clinicians eager for new therapies, given the long and often unpredictable path from discovery to impact?
There’s beauty in the science, but for patients, change still takes time. Survival remains poor, and radiation therapy is still a mainstay — something I’d never have imagined 30 years ago. Yet history shows that today’s basic science often seeds tomorrow’s breakthroughs. Ozempic, for instance, traces back 60 years to a peptide discovered in gila monster saliva.