High-grade gliomas remain among the most lethal human cancers, with few effective targeted therapies for either IDH-mutant or IDH-wildtype disease. Although recent advances such as brain-penetrant IDH inhibitors can delay progression in early-stage IDH-mutant gliomas, these tumors inevitably evolve into aggressive, treatment-refractory malignancies. A major limitation in the field is that most cancer gene discovery and drug target identification relies on in vitro screening approaches that fail to capture the complex metabolic, immune, and microenvironmental context of tumors in the brain. This ASPIRE Award addresses the overarching question of how to identify physiologically relevant cancer drivers and therapeutic vulnerabilities directly in vivo.
Building on newly developed in vivo CRISPR screening platforms from the Schramek lab, the team will systematically interrogate genetic dependencies in mouse and human models of IDH-mutant and IDH-wildtype high-grade glioma. Prior work using these technologies uncovered FGF21 as a previously unrecognized tumor suppressor and therapeutic vulnerability specific to IDH-mutant glioma, with compelling genetic, metabolic, and pharmacologic evidence of selective tumor cell killing. The project will define the molecular and metabolic mechanisms underlying this dependency, evaluate therapeutic strategies that activate FGF21 signaling in relevant glioma models, and extend in vivo CRISPR screening to uncover new actionable targets in IDH-wildtype glioblastoma.
By moving functional genomics into native tumor settings, this work has the potential to reveal new treatment strategies for glioma patients who currently face dismal outcomes and accelerate the development of more effective, biology-driven therapies.