Oral Presentation 36th Lorne Cancer Conference 2024

Elucidating the role of FGFR1 alterations in pediatric low-grade gliomas (#12)

April A Apfelbaum 1 , Sher Bahadur 1 , Eric Morin 1 , Dominik Sturm 2 , Dana Novikov 1 , Jeremy DiGiacomo 1 , Margaret M. Cusick 1 , Jayne Vogelzang 1 , Connor Bossi 1 , David Jones 2 , Keith Ligon 1 , Pratiti Bandopadhayay 1
  1. Dana Farber Cancer Institute, Boston, MA, United States
  2. German Cancer Research Center (DKFZ), Heidelberg, Germany

Pediatric brain cancers are the leading cause of cancer-related deaths in children. We (and others) have recently found that close to 10% of all pediatric gliomas, encompassing low-grade gliomas (LGGs) and high-grade gliomas (HGGs), harbor recurrent driver alterations in FGFR proteins, most frequently FGFR1, the gene encoding Fibroblast Growth Factor Receptor 11-4. FGFR1 is a receptor tyrosine kinase (RTK) that is critical for signal transduction through the MAPK, PI3K/mTOR, and JAK/STAT pathways and is commonly altered in many adult and pediatric cancers. In pediatric gliomas, FGFR1 alterations present as either structural variants (SVs), including kinase duplications and fusion proteins, or kinase-activating single nucleotide variants (SNVs). Recurrent FGFR1 alterations represent a promising therapeutic target for precision medicine approaches. We have generated isogenic mouse and human neural stem cell models driven by FGFR1 and BRAF alterations. We have found that these NSC lines grow independent of growth factors and form tumors in mice. Interestingly, RNA-sequencing of these lines revealed the FGFR1-altered lines are enriched in neuronal gene programs. The FGFR1-altered models exhibit increased sensitivity to multiple panFGFR inhibitors when compared to the BRAF-altered models. However, of the FGFR1-altered lines, the FGFR1 + PTPN11 co-occurring mutation line is the least sensitive which suggest combination therapies may be needed. Our studies provide key insights into the biology of FGFR1-altered gliomas and how to best therapeutically target them.

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