Every year, more than 14,000 Americans hear a diagnosis that changes everything. Glioblastoma. Brain cancer. Incurable. Most patients live roughly 15 months after receiving that diagnosis. Only 1 in 20 survive past five years, and existing treatment options do painfully little to shift those numbers. Surgery can remove part of a tumor, but glioblastoma weaves through brain tissue like roots through soil, making complete removal almost impossible. Chemotherapy and radiation may buy a few extra months, but they often exact a steep cost on quality of life. Some patients choose to skip treatment altogether, deciding that the side effects aren’t worth the marginal gain.
For decades, researchers have searched for something better. For decades, nothing has worked. But a team at the University of Virginia may have just cracked something open. By targeting the very gene that drives glioblastoma, they’ve identified a small molecule that, in mice, destroyed cancer cells while leaving healthy brain tissue untouched. And if future research confirms what early results suggest, the treatment might one day come as a simple pill.
How they got there, though, is a story that begins not with brain cancer at all, but with a rare disease that strikes children.
A Clue Hidden in a Childhood Cancer
Hui Li, a researcher in UVA’s Department of Pathology, wasn’t working on glioblastoma when his team caught the first hint of something unusual. They were studying rhabdomyosarcoma, a rare cancer that primarily affects children. Because childhood cancers tend to involve fewer genetic mutations than adult cancers, they can be easier to study at a molecular level, offering a clearer window into how specific genes behave when something goes wrong.
During that earlier work, Li’s team spotted an abnormality in a gene called AVIL. Curious about whether the same gene might be active in adult cancers, they expanded their research and found something striking. AVIL wasn’t just present in glioblastoma. It was overexpressed in every single glioblastoma cell they examined, and at even higher levels in glioblastoma stem cells, the hardiest and most dangerous type of tumor cells. Yet in normal, healthy brain tissue, AVIL barely registered.
In 2020, the team confirmed AVIL as the oncogene responsible for driving glioblastoma. An oncogene, put simply, is a normal gene that spirals out of control and causes cells to become cancerous. Under ordinary conditions, AVIL helps cells keep their size and shape by binding to a protein called actin. But when various factors push the gene into overdrive, it triggers cancer cells to form and multiply.
When Li’s team silenced AVIL in lab mice, the results were dramatic. Glioblastoma cells died. Healthy cells stayed completely intact. Knocking out the gene in mice produced no adverse effects at all, suggesting a wide gap between the dose needed to kill cancer and the dose that might harm a patient.
“The novel oncogene we discovered promises to be an Achilles’ heel of glioblastoma,” Li said at the time, “with its specific targeting potentially an effective approach for the treatment of the disease.”
From Gene to Molecule
Identifying the gene was a major step, but it was only half the puzzle. Silencing a gene inside a lab mouse and doing the same safely inside a human brain are two very different challenges. Li’s team had proven that blocking AVIL could wipe out glioblastoma cells, but the lab technique they used couldn’t be applied to people. So they set out to find something that could.
Using a method called high-throughput screening, the team rapidly tested large numbers of chemical compounds, searching for one that could shut down AVIL without causing harm to the rest of the body. After years of work, they identified a small molecule that fit. It binds directly to AVIL protein and stops it from latching onto actin, cutting off the chain of events that fuels tumor growth. In lab tests, the molecule triggered changes in gene expression that matched what happened when researchers silenced AVIL using more direct methods, a strong sign that it was hitting the right target.
Equally important, the team’s continued work confirmed just how central AVIL is to the disease. In the protein produced by the gene, the researchers found it was abundant in glioblastoma patients but barely present in healthy human brains. Every new piece of evidence pointed in the same direction.
Results of this latest research appeared in Science Translational Medicine, with funding from the National Institutes of Health and the Ben & Catherine Ivy Foundation.
Crossing Barriers Other Drugs Can’t
Plenty of experimental cancer drugs show early signs of working, only to fail when faced with the particular difficulties of treating brain tumors. What separates Li’s molecule from many others comes down to a handful of properties that, taken together, make for a very encouraging picture.
For starters, the compound targets a protein that glioblastoma cells depend on heavily, but that healthy brain cells barely produce. In mouse studies, it killed tumor cells while leaving normal astrocytes and neural stem cells alone. It also proved effective across five different glioblastoma mouse models, including tumors resistant to temozolomide, the standard chemotherapy drug used against glioblastoma today. Across all five models, researchers saw no harmful side effects.
Just as important, the molecule can cross the blood-brain barrier. Many drugs that fight cancer effectively in other parts of the body simply cannot get past this protective wall, which is a major reason why so many experimental treatments for brain tumors fail. Li’s compound clears that hurdle.
And for patients who may one day benefit from it, there’s one more encouraging detail. Rather than requiring injections or hospital visits, the compound could be taken by mouth, like any other prescription medication. “Glioblastoma is a devastating disease. Essentially no effective therapy exists,” Li said.
Promising, But Far From Finished
Before anyone can walk into a pharmacy and fill a prescription, a great deal of work remains. Researchers still need to optimize the molecule for safe use in humans, which means adjusting its chemical structure, testing how the body processes it, and confirming that it performs as expected outside of mouse models. After that, the compound would need to pass through multiple rounds of clinical trials, each designed to test safety and effectiveness in human volunteers, before the FDA could consider approval.
Li has already taken steps to move things forward beyond the lab. He founded a company called AVIL Therapeutics to develop AVIL inhibitors, and he and fellow researcher Zhongqiu Xie have secured a patent related to their approach. Support from institutions like UVA’s Paul and Diane Manning Institute of Biotechnology, which was created to speed up the development of treatments for the most difficult diseases, could also help shorten the distance between the lab bench and the patient’s bedside.
None of this will happen overnight. Drug development is a slow, expensive, and uncertain process, and many compounds that look great in mice never make it to people. But Li and his team believe the science behind their work gives them reason for cautious optimism.
A Crack in a Wall That Hasn’t Budged in Decades
Even with all those caveats, what Li’s team has accomplished represents a genuine step forward for a disease that has long resisted progress. Standard treatment for glioblastoma has barely changed in decades. Radiation combined with temozolomide, the current best option, added just 2.5 months of survival when it was first introduced, and doctors hailed even that modest improvement as a success. Since then, progress has been almost nonexistent.
Having both a clear cancer-driving target and a compound that can block it, cross the blood-brain barrier, and spare healthy cells is not something researchers in this field see every day. It doesn’t mean a cure is around the corner. But it does mean that, for the first time in a long while, there is a credible new path to follow. “GBM patients desperately need better options. Standard therapy hasn’t fundamentally changed in decades, and survival remains dismal,” Li said.
His team’s goal, he added, is to bring an entirely new way of fighting glioblastoma into the clinic, one built around a weakness in the cancer that no one has targeted before. For the thousands of patients diagnosed each year, that kind of ambition cannot come soon enough.
