Glioma is the most common and devastating malignancy of the central nervous system (CNS). We discovered that the majority of adult low-grade gliomas and secondary glioblastomas possess a hot spot mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1). One common feature of IDH1 mutations is a neomorphic enzymatic activity converting alpha-ketoglutarate (?) to 2-hydroxyglutarate (2HG), which impairs ?-dependent histone and DNA demethylases, resulting in global epigenetic changes. These discoveries have immediate clinical implications: they provide a genetic signature to augment conventional tumor classification and they aid in prognosis, treatment selection, and therapeutic trial design. While the deregulation of metabolism and epigenetics have emerged as phenomena associated with IDH1-mutated cells, the detailed connection between the IDH1 mutation and cellular biological phenotypes remains to be determined. The overall goals of our research are to understand the fundamental impact of IDH1 mutations on gliomagenesis and to evaluate therapeutic strategies of targeting mutant IDH1 itself and with other molecular pathways required by IDH1-mutated tumors. Based on our preliminary data, we have formulated a central hypothesis: mutant IDH1 and mutant IDH1-induced metabolic shifts are critical events underlying the development of IDH1-mutated glioma. The rationale for this study is that by identifying how mutant IDH1 initiates or promotes gliomagenesis, we will build a deeper understanding of brain cancer and its therapeutic vulnerabilities. Here we propose the following specific aims:
Aim 1) Dissect the impact of mutant IDH1 on tumor formation, progression and maintenance in biologically and genetically relevant model systems;
Aim 2) Achieve comprehensive and dynamic characterization of metabolic alterations in IDH1-mutated cells prior to and following mutant IDH1 targeting. To lay the foundation for these specific aims, we have developed genetically engineered mouse models expressing mutant IDH1 in the CNS. This will define the impact of mutant IDH1 in a biologically relevant context, one similar to that of human gliomas. We also have generated isogenic cell lines to dissect the impact of the IDH1 mutation on the cellular epigenome and metabolome. Additionally, we have successfully derived genetically faithful and clinically relevant glioma cell lines and xenograft models from IDH1-mutated gliomas allowing us to ascertain whether mutant IDH1 is a viable therapeutic target in glioma. Finally, we have used a small molecule specifically targeting mutant IDH1 to inhibit 2HG production allowing us to evaluate the therapeutic value and precise molecular consequences of targeting mutant IDH1 in these systems. Our work will improve the understanding of the interplay between genetic and metabolic events during oncogenesis, thereby opening an entirely new field of study.
In addition to providing new information about the basic pathogenic mechanism of gliomas, this research will also provide immediate clinical implications to contribute to the development of therapeutic interventions for this aggressive cancer. The results derived from this study have the potential to lead to greater understanding of cancer metabolism, which may yield insights for targeting other cancers,
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