Exploring p53-mediated ferroptosis to treat IDH1-mutant glioma

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Project Summary Malignant gliomas represent 81% of primary brain malignancy and cause significant morbidity and mortality. Despite the extensive characterization of malignant glioma at the molecular level, the knowledge has yet to significantly improve patient outcome. Molecular features, most notably IDH1 (isocitrate dehydrogenase 1) hotspot mutations at Arg132, are now an integral part of the WHO classification of gliomas because patients with IDH1 mutation show significantly better outcome than those without. IDH1 mutations are extremely prevalent in lower-grade glioma. Although IDH1 mutations have been identified in various types of cancer, our analysis of >45,000 human pan-cancer samples revealed that IDH1 mutations are rare events despite the prevalence of IDH1 mutations in glioma. Furthermore, co-occurrence of IDH1 mutation and TP53 alteration is virtually exclusive in glioma. The requirement of TP53 alteration for IDH1-mutant glioma genesis has been demonstrated in mouse models, but the underlying mechanism remains unknown. Recent studies discovered that p53-mediated ferroptosis—a newly recognized form of cell death resulting from lipid peroxidation—is critical for tumor suppression. Given the sensitivity of IDH1-mutant glioma to redox and ferroptosis, we hypothesize that TP53 alteration is crucial to IDH1-mutant glioma by inhibiting ferroptosis whereas p53 reactivation specifically sensitizes IDH1-mutant glioma to ferroptosis. Our long-term goal is to provide a mechanistic understanding of the role of TP53 mutation in IDH1-mutant gliomagenesis and to identify novel targets in preclinical models to improve glioma treatment. In this project, we will investigate the tissue-specific role of TP53 mutation in IDH1-mutant gliomagenesis and repurpose FDA-approved drug for precision reactivation of p53 mutants in glioma. The proposed studies will fill the knowledge gap in the understanding of tissue-specific role of TP53 mutations in IDH1-mutant gliomagenesis through the investigation of p53-mediated ferroptosis and provide novel insight into the unique vulnerability of IDH1-mutant glioma to be explored for precision treatment. Our generated reagents will provide a valuable resource for the wider scientific community to pursue further research.