Despite decades worth of research, glioblastoma remains one of the most lethal cancers. The identification of IDH1 as a major cancer gene in glioblastoma provides a great opportunity for improving our understanding, diagnostics and treatment of this disease. Recent studies from our laboratory characterized the genetic landscape of gliomas and have shown the cooperation between IDH1 mutations and other oncogenic alterations including TP53 mutations. Normally, IDH1 functions in the oxidative decarboxylation of isocitrate to α-ketoglutarate, however, the mutant form confers neomorphic enzymatic activity by producing D-2-hydroxyglutarate, an oncometabolite responsible for aberrant methylation in IDH1-mutated tumors. To determine the role of mutant IDH1 in vivo, we generated a conditional knockin mouse model that produces D-2-hydroxyglutarate. This genetically faithful system is biologically and clinically relevant and will promote the understanding of mutant IDH1-mediated tumorigenesis while offering a route for therapeutic targeting.

We observed that broad expression of mutant IDH1 throughout the brain leads to hydrocephalus in 80% of animals. To obviate these deleterious effects, we restricted expression of mutant IDH1 to the neural stem cell population. Animals were sacrificed after one year, at which time we observed mild hydrocephalus in several animals. Recapitulating the genetics of human tumors, we sought to determine the synergistic effects between mutant IDH1 and deletion of P53. We observed development of low- and high-grade gliomas in approximately 14% of animals. Tumors developed in both P53 deleted animals as well as in mutant IDH1/P53 deleted animals, with mutant IDH1 expressed in tumors of the latter cohort. Differences in latency, penetrance, differentiation, and epigenetic modifications are being assessed. Additionally, we are determining the cell fate of IDH1-mutant cells over time to assess the biological effects of the mutation on the behavior and differentiation of neural stem cells. Lastly, to decrease the latency and increase the penetrance of tumor formation, an orthotopic intracranial injection model is being generated to allow for visualization of tumor formation and development, as well as investigation of therapeutic modalities. Understanding the biological effects of the most common mutations found in gliomas will bring us strides closer to determining mechanisms and therapeutic targets for IDH1-mutated cancers.

Citation Format: Christopher J. Pirozzi, Catherine Y. Wang, Austin B. Carpenter, Huishan Zhu, Paula K. Greer, Roger E. McLendon, Darell D. Bigner, Yiping He, Hai Yan. Driving brain tumorigenesis: Generation of a mutant IDH1 mouse model of progressive glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 63. doi:10.1158/1538-7445.AM2014-63