A collaborative study between Dana-Farber Cancer Institute and the Broad Institute found that 8.9% of children with glioma, the most common type of pediatric brain tumor, have alterations in the fibroblast growth factor receptor (FGFR) family of proteins, and these gliomas may be sensitive to existing U.S. Food and Drug Administration (FDA)-approved inhibitors that broadly block FGFR. These findings were published by Apfelbaum et al in Nature Communications.
The work opens the door to potential targeted therapeutic regimens for these tumors, particularly for pediatric low-grade gliomas [pLGG], though more research is needed to improve the efficacy of these treatments and to test them in pediatric clinical trials. Currently, there are no FDA-approved therapies or clinical trials specifically for FGFR-altered pediatric gliomas.
“This research was motivated by the patients we see in our Jimmy Fund Clinic 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,” said co-senior author Pratiti (Mimi) Bandopadhayay, MBBS, PhD, a physician-scientist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and an institute member at Broad. “The results of this study have given us insights that will impact children with FGFR-altered gliomas seeking care in the clinic today.”
Similar research led to the 2024 approval of tovorafenib, a small-molecule inhibitor of RAF kinase, for childhood BRAF-altered gliomas. “We’re following that same strategy with this research but with a focus on FGFR-altered pediatric gliomas,” said Dr. Bandopadhayay. “It is a real area of need for families.”
Study Details
The research team performed genomic analyses on 11,635 gliomas from three existing data sets across all ages. The analysis revealed that 8.9% of pediatric gliomas harbor FGFR alterations. The most common alterations found were in the FGFR1 and FGFR2 genes and included both point mutations and structural variants. The team concluded that FGFR1-altered pLGGs were the most frequent subgroup of FGFR-altered gliomas in children.
Co-first authors April Apfelbaum, PhD, and Eric Morin, MD, PhD, postdoctoral fellows in Dr. Bandopadhayay's lab, leveraged the genomic data to develop the first-ever models of FGFR-altered gliomas consisting of spherical collections of living FGFR-altered neural stem cells. They used the models to determine that FGFR alterations may induce the development of the tumors. Tests of FGFR inhibitors in the preclinical models showed that the tumors were sensitive to the inhibitors.
“[These are] the first preclinical data showing that existing FGFR inhibitors might be viable therapeutics for FGFR-altered pediatric gliomas,” said Dr. Apfelbaum.
They followed their preclinical model tests with a retrospective look at a small number of cases of pediatric patients with FGFR-altered gliomas who were treated with FGFR inhibitors. They found that patients with pLGGs frequently experienced stable disease after treatment with these medicines.
Pediatric LGGs are the most common central nervous system cancer among children. Patients typically survive into adulthood after treatment because the tumors stop growing over time, but current standard treatment of chemotherapy and surgery may result in long-term challenges including mental health disorders, vision changes or loss, seizures, and behavioral challenges.
“We are eager to find precision medicines with fewer side effects than current standard-of-care treatment for these patients,” emphasized Dr. Bandopadhayay.
The team plans continued research to improve the efficacy and brain penetrance of FGFR inhibitors and to test these medicines in clinical trials. They also plan to investigate their finding that FGFR expression may play a role in normal brain development to determine whether that finding should influence treatment strategies.
Disclosure: For full disclosures of the study authors, visit nature.com.
