Molecular Mechanisms of Mutant IDH inhibition and DNA Damage in IDH-mutant Glioma

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Project Summary/Abstract: Gliomas are the most common primary brain tumors in adults, a subset of which have mutations in the metabolic gene isocitrate dehydrogenase 1 (IDH1). Cancer-associated IDH1 mutants (the most common of which is IDH1R132H) are neomorphs that produce the oncometabolite 2-hydroxyglutarate [(R)-2HG], which is thought to contribute to glioma formation. The mutant IDH (mIDH) inhibitor vorasidenib has been recently FDA approved for the treatment of select IDH-mutant glioma patients and is poised to become standard-of-care. However, response to mIDH inhibitors is heterogeneous, and our understanding of how these drugs work in glioma has been severely limited by a lack of faithful animal models that respond to mIDH inhibition. Existing IDH-mutant glioma mouse models require xenograft transplantation, model high-grade (mIDH inhibitor-resistant) disease, and/or incorporate mutations that are not frequently observed in lower-grade IDH-mutant gliomas. In an effort to better understand these unanswered questions regarding mIDH1 biology, I made a genetically engineered mouse (GEM) model of mIDH1-driven grade 3 astrocytoma that circumvents key limitations of existing models and responds to mIDH inhibitor treatment. I leveraged this GEM and other models to show that IDH-mutant gliomas are sensitive to de novo pyrimidine synthesis inhibitors (e.g. dihydroorotate dehydrogenase (DHODH) inhibitors) due to an increased susceptibility of IDH-mutant cells to replication stress caused by these drugs. My overall objective is to use my mIDH inhibitor-responsive glioma GEM to address translationally relevant questions in glioma. In Aim 1, we will use single cell multiomics sequencing technologies and functional genomic screening to understand mechanisms underlying response to mIDH inhibitors in glioma. This will include both characterization of transcriptomic and epigenomic changes induced by mIDH inhibition, as well as unbiased studies to identify transcriptional alterations that are functionally relevant for treatment response. In Aim 2, we will leverage the immunocompetent and autochthonous status of our GEM to identify microenvironmental interactions driven by mIDH and transcriptional alterations induced by mIDH inhibition in the immune microenvironment. In Aim 3, we will assess how mIDH impacts efficacy of DNA damaging therapies (including standard-of-care radiation and alkylating chemotherapies) and identify mechanisms underlying sensitivity of IDH-mutant gliomas to DNA damage caused by replication stress (such as DHODH inhibition). My long-term goal is to understand how mIDH alters glioma biology in order to develop new effective treatment options for this disease. Results from my Aims will identify biomarkers and mechanisms of response to mIDH inhibition, nominate combination therapeutic strategies, and reveal mechanistic insights on how mIDH alters the response to DNA damage. The research proposed here will directly inform how patients with IDH- mutant glioma are treated in the clinic and also reveal fundamental insights on clinically relevant epigenomic and microenvironmental reprogramming in IDH-mutant glioma.