Cracking the Code

The Science Driving New Possibilities for Children With Brain Tumors

"I'll give it one day," Mariella Filbin, MD, PhD, told her mentor.

It was 2014 and Filbin was a hematology/oncology fellow specializing in pediatric brain cancer. Her mentor, David Williams, MD, now president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, chief of hematology/oncology at Boston Children's Hospital, and Leland Fikes Professor of Pediatrics at Harvard Medical School, wanted her to go to a lab at the Massachusetts Institute of Technology (MIT) for the research portion of her fellowship. But Filbin had already established herself in a Dana-Farber lab. She didn't want to be anywhere else.

Williams kept encouraging her.

"He said, 'When I was your age, one of my mentors told me to go to MIT, and it set up my career,'" recalls Filbin.

She agreed to spend just one day across the river in Cambridge visiting laboratories. If she didn't see anything interesting, she would come back.

She stayed for three years.

The talk that captivated her in her initial visit to MIT described a new technology called single cell RNA sequencing, which reveals which genes in an individual cell are turned on or off and at what level, providing a picture of a cell's identity and behavior.

"This is the lens we need to look at our patients' tumors and finally get into the real biology that drives them," Filbin remembers thinking.

Today, as co-director of the Dana-Farber/Boston Children's Pediatric Neuro-Oncology Program together with Susan Chi, MD, she uses that technology regularly in her Dana-Farber laboratory where she focuses on pediatric high-grade gliomas, which are incurable brain tumors with median survival times less than 18 months after initial diagnosis. That technology was and remains — as she predicted — key to understanding these cancers and finding more effective therapies for children diagnosed with them. 

"Technology has enabled incredible scientific discoveries in our field," says Kimberly Stegmaier, MD, chair of Pediatric Oncology. "It is remarkable how we have been able to apply new technologies to understanding the biology of these cancers and to ultimately matching them to therapies."

Back in 2014, there were no targeted therapies approved for childhood brain cancers. Now there are a few, with more on the radar, some of which are based on exciting new T cell therapies — and almost all of which have deep roots in Dana-Farber science. These advances are the products of persistent efforts by physician-scientists like Filbin who see the toll these cancers take on children and families.

"Patients are the inspiration. If you work closely with these children, the need to change something is apparent. You just cannot live without doing something about it," says Filbin, who also cares for children with brain cancer. "The question is, where do you start?"

Mapping Tumor Behavior

Filbin successfully brought single cell RNA sequencing into the field of pediatric brain cancer, but her efforts to do so would have been impossible without advances made fifteen years ago.

In 2010, no one biopsied children with high-risk brain cancer. It was hardly even discussed, until Mark Kieran, MD, PhD, a pediatric oncologist then at Dana-Farber, raised it with anyone who would listen. His work led to a practice of collecting miniscule brain tumor samples from certain patients prior to surgery.

The challenge for Filbin was that these samples were tiny, smaller than a grain of rice. But single cell RNA sequencing technology wasn't made for small samples, and her colleagues at MIT were not optimistic that it would work.

Filbin, however, wanted to see the inner workings of each individual cell and she needed this new technology to do it. Without it, the only option was to grind up tumor samples and look at the signals in the resulting soup of material. This data could provide clues about what kinds of cells, mutations, and proteins were in the sample, but revealed nothing about individual cells.

"I wanted a snapshot of the whole ecosystem, to see not just what the cells are but how they talk to each other and what they do to thrive," Filbin says. "We needed this technology to work."

Her first two attempts failed. But the third attempt, after a year and a half of effort, yielded results. Filbin dropped everything and focused on refining the process.

By 2018, she had analyzed seven samples from patients with a form of high-grade glioma and began to see a pattern. In 2022, her analysis of 50 patients sharpened the picture.

What she observed is not fully understood, but one thing stood out: Some of the tumor cells end up in a vicious growth cycle spurred on by a protein called platelet derived growth factor alpha (PDGFRA). The protein is overactive in about 15 percent of pediatric high-grade gliomas.

It so happens that a drug called avapritinib, which is already approved by the U.S. Food and Drug Administration (FDA) for adults, blocks PDGFRA. Filbin moved on this data quickly and, along with clinical partners, conducted a first-ever clinical test of avapritinib in pediatric and young patients with a form of high-grade glioma in 2025.

They found that the drug was generally safe and resulted in tumor reduction visible on brain scans in three out of seven patients who had previously relapsed and been treated with chemotherapy and radiation multiple times.

Next, Filbin says, "we want to go up front and see how this drug performs in patients whose tumors haven't been altered by so many previous therapies."

Targeting Tumor Drivers

Dana-Farber investigators are also making progress in pediatric low-grade gliomas. These tumors grow during childhood but tend to stop as children become young adults. Most children survive treatment, which may include surgery, chemotherapy, and radiation, but many live with neurological, hormonal, visual, or other problems the rest of their lives.

In 2024, the FDA approved the use of tovorafenib, a targeted therapy for certain forms of pediatric low-grade gliomas. Tracing this advance to its roots leads all the way back to 1976, when Charles Stiles, PhD, came to Dana-Farber. Stiles was among the researchers who first discovered oncogenes, single gene mutations that turn on uncontrolled cell growth.

"Before we knew that, we were like the proverbial blind men feeling different parts of an elephant," says Stiles. "Over the years, we suddenly saw the whole elephant."

The question of which oncogenes might be driving pediatric low-grade gliomas inspired the formation of the Pediatric Low-Grade Astrocytoma (PLGA) program at Dana-Farber in 2007. With $2 million in funding from families with children who were being treated at Dana-Farber, the quest was on to find and block an oncogene for these cancers.

Teams outside of Dana-Farber discovered that mutations in a gene called BRAF were common in children with low-grade gliomas. This led to the approval of the first targeted medicines designed to defeat BRAF-mutant proteins for these childhood cancers, but they didn't work for all children.

Stiles kept investigating and around 2017 he found that the existing BRAF-targeted medicines would not work against the most common mutation in pLGGs — BRAF fusions. In fact, the medicines had the potential to cause the cancer to grow. New drugs were needed.

Additional efforts by Stiles and colleagues identified a medicine called tovorafenib that inhibited the oncoprotein in these brain cancers and shut them down. A small clinical trial resulted in the FDA's designation of the drug as a "breakthrough therapy" in 2020 and full approval in 2024.

"This is a really nice example of just how much preclinical work goes into a discovery like this one," says Karen Wright, MD, MS, a clinician-scientist in the Childhood Brain Tumor Center who helped initiate the early phase clinical trials. "An approval for a pediatric tumor doesn't happen very often."

Building Better Models

Today, Dana-Farber physician-scientist Pratiti (Mimi) Bandopadhayay, MBBS, PhD, director of the PLGA program at Dana-Farber, is working with other scientists within the program to continue to find new targets and therapies for children with pediatric low-grade gliomas and related brain tumors. Bandopadhayay uses bulk and single cell DNA sequencing, RNA sequencing, and epigenetic analyses to study pediatric gliomas in her lab, and high-throughput functional assays using technologies such as CRISPR to edit DNA inside cancer cells to help understand the function of individual genes.

When she finds an interesting lead, such as a mutation that appears only in tumor cells, she pressure-tests it to learn more about what its role might be in the formation of the cancer. Recently, for example, she and her team found that 9 percent of children with glioma have alterations in the fibroblast growth factor receptor (FGFR) family of proteins.

To understand more about FGFR alterations, her team grew the first-ever FGFR-altered glioma models in the lab. Using these models, her team found that FGFR mutations were sufficient to cause gliomas to form.

"Often it's just one driver that happens at a stage of development when it shouldn't, and then locks the cells into a developmental state of rapid growth," says Bandopadhayay.

The team also used these models to show that low-grade gliomas may be sensitive to existing FDA-approved inhibitors that broadly block FGFR. This research is helping clinicians make decisions about when and how to use these inhibitors in patients today and inspiring additional research within the Pediatric Low-Grade Astrocytoma program to improve them.

"This research was motivated by the patients that we see and others around the world who have been diagnosed with pediatric gliomas with FGFR-alterations and want to know if existing targeted medicines are an option," says Bandopadhayay. "We are eager to find precision medicines with fewer side effects than current standard of care treatment for these patients."

By Beth Dougherty