A collaborative study between Dana-Farber Cancer Institute and the Broad Institute has identified promising therapeutic targets for pediatric brain tumors, revealing that existing FDA-approved FGFR inhibitors may offer new treatment options for children with these challenging cancers. The research, published in Nature Communications, demonstrates significant potential for precision medicine approaches in pediatric neuro-oncology.
FGFR Alterations Common in Pediatric Gliomas
Through genomic analysis of 11,635 gliomas across all ages from three existing datasets, researchers discovered that 8.9% of pediatric gliomas harbor alterations in the fibroblast growth factor receptor (FGFR) family of proteins. The most common alterations were found in the FGFR1 and FGFR2 genes, including both point mutations and structural variants, with FGFR1-altered pediatric low-grade gliomas (pLGGs) representing the most frequent subgroup.
"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," says co-senior author Pratiti (Mimi) Bandopadhayay, MBBS, PhD, a physician-scientist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center.
Breakthrough Preclinical Models Demonstrate Drug Sensitivity
Co-first authors April Apfelbaum, PhD, and Eric Morin, MD, PhD, developed the first-ever models of FGFR-altered gliomas using spherical collections of living FGFR-altered neural stem cells. These innovative models allowed researchers to determine that FGFR alterations can induce tumor development and, crucially, that these tumors show sensitivity to FGFR inhibitors.
"This is the first preclinical data showing that existing FGFR inhibitors might be viable therapeutics for FGFR-altered pediatric gliomas," says Apfelbaum.
Clinical Evidence Supports Therapeutic Potential
The research team conducted a retrospective analysis of pediatric patients with FGFR-altered gliomas who received treatment with FGFR inhibitors. The results showed that patients with pLGGs frequently experienced stable disease after treatment with these medicines, providing clinical validation for the preclinical findings.
Currently, no FDA-approved therapies or clinical trials exist specifically for FGFR-altered pediatric gliomas, making this research particularly significant for addressing an urgent unmet medical need.
Addressing Treatment Challenges in Pediatric Brain Cancer
Pediatric low-grade gliomas represent the most common central nervous system cancer among children. While patients typically survive into adulthood because tumors often stop growing over time, current standard treatments involving chemotherapy and surgery result in significant long-term challenges including mental health disorders, vision changes or loss, seizures, and behavioral problems.
"We are eager to find precision medicines with fewer side effects than current standard of care treatment for these patients," says Bandopadhayay.
Expanding to Rare Pediatric Brain Tumors
The research extends beyond gliomas to other rare pediatric brain cancers. Researchers from Dana-Farber/Boston Children's Cancer and Blood Disorders Center, in collaboration with the Broad Institute, have also identified potential therapeutic targets for embryonal tumor with multilayered rosettes (ETMR), a rare and aggressive brain tumor primarily affecting young children.
The ETMR research focused on genetic vulnerabilities within tumor cells and discovered that FGFR signaling pathways play a critical role in tumor growth. Using FDA-approved FGFR inhibitors in preclinical models showed promising results, marking a significant step toward understanding ETMR's underlying mechanisms.
Future Research Directions
The research team plans to continue investigating ways to improve the efficacy and brain penetrance of FGFR inhibitors and to test these medicines in clinical trials. They also intend to explore their finding that FGFR expression may play a role in normal brain development to determine if this should influence treatment strategies.
This work follows a similar successful strategy that led to the recent approval of tovorafenib for childhood BRAF-altered gliomas, demonstrating the potential for translating preclinical discoveries into approved therapies for pediatric brain cancer patients.
