Abstract B020: Preclinical investigation of FGFR inhibitors in pediatric low-grade gliomas

Pediatric brain cancers are the leading cause of cancer-related deaths in children. We (and others) have reported that close to 10% of all pediatric gliomas, encompassing low-grade and high-grade gliomas, harbor recurrent drive alterations in Fibroblast Growth Factor Receptor proteins (FGFR). In pediatric low-grade gliomas FGFR1 alterations are the most common and occur as structural variants, including kinase duplications and fusion proteins, or kinase-activating single nucleotide variants. Recurrent FGFR1 alterations and the existence of multiple FDA-approved (for adult) pan-FGFR inhibitors represent an attractive therapeutic target for precision medicine approaches, however a challenge with FGFR inhibitors has been the toxicities associated with them and the lack of clinical trials in children. A major aim of this project is to identify the best preclinical FGFR inhibitor candidates for these patients. To address this, we have generated isogenic mouse and human neural stem cells models driven by FGFR1 and BRAF alterations found in pLGGS. We have found that these models grow independent of growth factor and form tumors in mice. The FGFR1-altered models exhibit sensitivity to MEK inhibitors. They also exhibit efficacy to panFGFR inhibitors in vitro and in vivo. We are currently testing the PK characteristics and blood brain barrier efficacy of all available FGFR inhibitors to inform the best candidate for early phase clinical trials. Overall, this project aims to perform preclinical testing using our novel isogenic models to determine a candidate FGFR inhibitor for patients with pLGGs. Citation Format: April A Apfelbaum, Sangita Pal, Sarah W Lamson, Eric Morin, Georges Ayoub, Sher Bahadur, Jeromy DiGiacomo, Margaret M Cusick, Prem Prabhakar, Connor C Bossi, Sehee Oh, Hyesung Jeon, Jinhua Wang, Hong Yue, Yuan Xiong, Amy Cameron, Patrick Rechter, Quang-De Nguyen, Sara J. Buhrlage, Eric S Fischer, Michael J Eck, Keith L Ligon, Pratiti Bandopadhayay. Preclinical investigation of FGFR inhibitors in pediatric low-grade gliomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr B020.