By studying patients who outlive their prognosis, scientists are learning how glioblastoma spreads, adapts and might finally be contained.

When Kyle Donohue was diagnosed with glioblastoma, the most aggressive form of brain cancer, in spring 2021, she was given about a year to live.

Almost five years and an experimental virus-based therapy later, the 56-year-old is living a full life, painting seascapes in her basement studio on Boston’s South Shore and enjoying walks along the Massachusetts coast. “I’ve always maintained a positive outlook that this is going to be OK,” says Donohue, who still wears a patterned headscarf as a nod to her battle with the disease.

Such patients — doctors call them “long-term survivors” — are rare. But they aren’t just statistical outliers. Researchers are studying them closely, searching for clues about why a disease that almost always kills within months sometimes doesn’t. Cases like Donohue’s have forced scientists to reconsider long-held assumptions about glioblastoma itself and what distinguishes patients who outlive their prognosis.

Glioblastoma has traditionally been treated as a mass of malignant cells to be cut out, blasted with radiation or poisoned with chemotherapy. Over the past decade Michelle Monje of Stanford University’s School of Medicine and Frank Winkler of Heidelberg University Hospital have uncovered evidence that glioblastoma cells don’t just sit in the brain — they connect to it, forming direct links with nearby neurons and tapping into electrical and chemical signals that help the tumor grow, spread and evade immune defenses.

“It’s really insidious, but this is what we have to disrupt,” says Monje, a professor of pediatric neuro-oncology. “We have to take away the cancer’s ability to be stimulated by the electrical activity of the nervous system.”

Winkler’s team in Germany observed the same behavior, and when he and Monje compared notes, they realized they had independently discovered the same phenomenon: tumors that “think.” “It’s as if a new brain forms inside the existing one,” says Winkler, who has watched tumor cells connect through hair-thin tubes that pass signals between them. “This new brain is capable of really dramatic things — something that you can even call ‘intelligence.’”

This wiring helps explain why surgery, chemotherapy, radiation and even powerful immunotherapies have shown only modest survival benefits. Glioblastoma behaves less like a localized mass and more like a distributed neural system that can reroute around damage. That adaptive network, Winkler argues, is the cancer’s ultimate defense mechanism. His lab has gone further, identifying a handful of “pacemaker” cells that appear to set the rhythm for the entire tumor. Blocking those cells in mice slowed growth and destroyed large parts of the network.

Winkler’s group is leading three multicenter trials in Germany: one testing the epilepsy drug perampanel to disrupt the neuron-to-cancer synapses that feed glioblastoma; another using meclofenamate, an anti-inflammatory that blocks communication between tumor cells; and a third combining radiation therapy with senicapoc, a drug that blocks ion channels used by the tumor’s pacemaker cells, weakening the cancer’s internal signaling and potentially making tumors more vulnerable to radiation.

“Disconnecting these malignant neural networks and then making standard therapies dramatically more effective — that’s the way to go,” Winkler says.

If any of these approaches succeed, they could mark the first major advance in glioblastoma treatment in two decades and establish a new pillar of cancer medicine.

As scientists deepen their understanding of glioblastoma’s biology, the search has widened to unconventional strategies, including virus-based therapies that aim to trigger an immune response inside the tumor. Donohue took part in one such experimental trial — and her unusually long survival is helping guide the design of future treatments.

The mother of two adult sons, Donohue was diagnosed with glioblastoma in March 2021 and underwent surgery followed by months of chemotherapy and radiation — the standard frontline regimen for the disease. When a routine MRI scan in December 2021 showed her cancer had recurred, she joined a trial at the Dana-Farber Brigham Cancer Center, taking the last available slot. In February 2022, she received a one-time infusion of CAN-3110, an experimental genetically modified herpes virus designed to kill cancer cells and train the immune system to recognize them. Her husband, Jim, was with her at the hospital.

“I got the herpes virus,” she says, laughing. “Jim and I were like, we’ve spent our whole lives trying to stay away from that, and now you’re injecting it into my head?”

Her first scan after the infusion showed the tumor was shrinking. Months later it was gone. Every three months she returns to Boston’s Brigham and Women’s Hospital for an MRI, and the scans remain clear. Neurosurgeon Antonio Chiocca, who removed Donohue’s tumor in 2021 and is leading the trial, says such outcomes underscore the importance of perseverance — for doctors and patients alike. “Taking somebody’s hope away is the worst thing you can do,” he says. “I always tell people, you could be one of the lucky ones. If it’s not a cure, at least we give you the gift of time.”

For Monje, the emerging biology explains glioblastoma’s resistance and informs the path forward. Her lab is exploring how to safely block the electrical currents that drive tumor growth, potentially using drugs developed for epilepsy and other neurological disorders. The work is also reshaping how researchers think about cancer more broadly. Nerve fibers and electrical signaling appear to influence tumors throughout the body, including in the stomach, prostate and lungs. Monje says similar circuitry-dependent growth has been seen in several of these cancers, underscoring the nervous system’s long-overlooked role as a regulator of tumor behavior.

“Now we know the monster we’re dealing with,” says Monje, who in 2025 shared the €1.3 million ($1.5 million) Brain Prize with Winkler for their pioneering work. “Now that we understand it, we can figure out its true vulnerabilities and fight it more effectively.”

Scientists are also beginning to probe a question that has long been difficult to study: whether a patient’s emotional state might alter the neural activity that fuels glioblastoma’s growth. Winkler has studied five patients who survived far longer than expected. All showed an unusually calm response from the moment of diagnosis, telling him that they felt “completely unafraid” of the disease and followed routines centered on meditation, painting, music or other relaxation techniques. He’s asked them to document such habits so he can assess them in larger cohorts.

While the idea may seem speculative, it aligns with a broader pattern in cancer research. Stress hormones such as adrenaline, noradrenaline and cortisol have been shown to promote tumor growth and relapse in other cancers, and early work suggests similar biological mechanisms may also be involved in glioblastoma. Anxiety, stress and pain can amplify neural activity and dampen immune defenses, creating conditions that favor tumor growth, while lower physiological stress may have the opposite effect.

“It sounds a little bit wild,” says Winkler. “But at the moment it’s the best explanation I have for these long-term survivors.”

In Chiocca’s trial, patients who lived longer tended to have tumors with higher numbers of T cells, immune cells that attack infected or abnormal cells. While he said he can’t explain Winkler’s observation about unusually calm patients, chronic stress is known to suppress immune responses by keeping the body in a prolonged fight-or-flight state — making the idea biologically plausible, though far from settled.

For Donohue, the science remains largely abstract. What she knows is that nearly five years after being told she had a year to live, her scans remain clear. She keeps painting. She keeps walking the coast. And her survival — once considered an anomaly — is being studied so that other cancer patients may outlive their prognosis too.

Written by: Jason Gale @Bloomberg

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