Abstract B023: Identifying effective targeted inhibitors as single-agents or in combination for FGFR1-altered pediatric low-grade gliomas

Abstract Pediatric low-grade gliomas (pLGGs) are the most common type of brain tumor in children. We (and others) have found that the second most common alteration in pLGGs is in Fibroblast Growth Factor Receptor 1 (FGFR1). Current treatment options for patients with pLGGs are surgical resection, chemotherapy, and targeted inhibitors. Despite the prevalence of FGFR1 alterations, the only approved targeted therapies in pLGGs are MEK and BRAF inhibitors, not FGFR inhibitors. Therefore, identifying effective therapeutic strategies for FGFR1-altered gliomas remains a large gap in the field. To investigate this question, we generated novel human isogenic neural stem cell lines that are driven by FGFR1-alterations found in pLGGs. Using these models, we have found that single agent treatment with currently available FGFR-inhibitors is unlikely to result in curative responses, and that combination approaches are likely. The goal of this project is to identify combination approaches that induce cytotoxic responses rather than those that are primarily cytostatic. To do so, we will leverage CRISPR-cas screening approaches to identify genes, which when ablated in the presence of FGFR-inhibitors, induce apoptosis. We have designed CRISPR-cas12a based lentiviral libraries that specifically target genes that are clinically druggable with current agents or are predicted to be druggable. We will transduce our isogenic FGFR-driven cell lines with the “druggable genome library” and then will isolate apoptotic cells using Annexin V labeling. This will allow us to evaluate which genes were ablated in cells in which apoptosis was induced, thereby nominating potential genes to target in combination approaches. Overall, this project aims to identify effective potential combination therapies for FGFR1-altered pLGGs. Citation Format: Sarah W Lamson, April A Apfelbaum, Anna Borgenvik, Noelia Ares Bovida, Verónica Rendo, Allison Uebele, John Doench, Pratiti Bandopadhayay. Identifying effective targeted inhibitors as single-agents or in combination for FGFR1-altered 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 (18Suppl₂): Abstract nr B023.