Cellular Variation Strengthens Tumors

According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, 77% of brain cancers are localized, which means that they remain confined to the brain. Collectively, all types of brain cancers have a 5-year survival rate of 33%. Piccirillo says that the 5-year survival rate for glioblastoma, however, is 7.0%.

The survival rate is low because glioblastoma almost always grows back, she says. Even after surgery, radiation, and chemotherapy, the tumors find a way to return. And often, surgeons cannot safely remove all the tumors.

In earlier research, Piccirillo demonstrated that cells in glioblastoma tumors are different from one another, even within the same tumor, and that their extreme heterogeneity enables the tumor to come back.

This extreme variation of glioblastoma cells is exactly why Piccirillo thinks the tumors are prone to recurring: although some cells respond to therapy, others do not. And these surviving cells, she explained, can not only restart a tumor but also resist previous therapies, making the recurrent tumors very difficult to treat.

To isolate cells from tumors that could not be fully removed from patients, Piccirillo and her team used a fluorescent molecule to identify tumor cells during surgery. The fluorescent molecule was given to patients before surgery. During surgery, the molecule made tumor cells light up, enabling neurosurgeons to distinguish between brain regions that were abundant in tumor cells and regions that were mostly non-tumor cells. The neurosurgeon could then collect tissues from the regions they could not fully remove but that were replete with tumor cells.

Piccirillo used these surviving glioblastoma cells from patients to further develop her menu of treatments. But she knew the tumors would return and would be deadly when they did.

Taking a Deeper Look in the Reservoir

Piccirillo’s team found that in 65% of people with glioblastoma, unremoved tumor cells reside in a specific brain region called the sub-ventricular zone. Its role as a reservoir of glioblastoma cells was described in the team’s research article, “Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma,” that was published in Cell Reports in January 2025.

Piccirillo’s research on the sub-ventricular zone highlighted a second important factor in glioblastoma recurrence: microglia, the immune cells that surround the residual glioblastoma cells. Microglia normally collect and remove waste from brain cells and help to defend the brain against cancer and infection. Piccirillo found that in the sub-ventricular zone, microglia help glioblastoma tumors to grow.

Possible Opportunities in the Electric Field

For her most recent research, Piccirillo used an AACR-Novocure grant, and the donated brain.

She and her team received tissue samples from the brain tumors, their edges, and the sub-ventricular zone and then isolated tumor cells from these tissues. Next, they genetically characterized these tumor cells and treated them with an electric field to compare how cells from each region responded.

Electric field therapy has been shown to extend survival of brain cancer patients. The treatment, developed by Novocure, uses an electrode-studded cap that patients apply to their shaved heads. Through this head-cap, a generator delivers electricity to the brain, bathing the head in an electric field.

Patients are encouraged to wear the head-cap for as many hours per day as possible because the electric field kills the fast-growing tumor cells. But some patients have reported that the cap feels hot, and others have stated that they don’t want to keep their heads shaved.

Piccirillo also points out that the treatment only delays recurrence; it does not prevent glioblastoma from returning.

“The therapy slows the brain cancer,” Piccirillo says. “It’s proven to extend survival. But that’s not enough. We want to keep glioblastoma from coming back.”

Electric field therapy is now part of the standard of care for glioblastoma, Piccirillo says. It is usually offered to patients in addition to surgery, radiation and chemotherapy, she says, but the treatment is not available in every country and not every patient can tolerate it.

Despite its inclusion in the standard of care, the mechanisms of action of electric field therapy — the biological bases of why these tumor-treating electric fields work — remain murky. So Piccirillo studied how tumor cells from different brain regions responded to electric field therapy.

Her research showed that glioblastoma cells isolated from the sub-ventricular zone differed from the glioblastoma cells isolated from tumors and tumor edges. The cells differed in their genetics and in their RNA transcripts, which are molecules that the cell uses to create proteins. Piccirillo is studying these differences to learn which might cause the cells to respond differently to the electric field therapy.

Looking Ahead: Treatments to Prevent Recurrence

Piccirillo is now searching for ways in which the electric field makes glioblastoma cells vulnerable to existing drugs and other therapies. Using that information, she then plans to develop personalized approaches to keep glioblastoma from coming back.