Targeting the IDH Pathway

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Targeted therapeutics designed against specific oncogenic genomic alterations have had a large clinical impact. Recently, large-scale sequencing studies have identified recurrent, gain-of-function IDH gene mutations in a significant subset of glioblastomas, with particular enrichment in malignant gliomas of younger adults (age 18-45). The mutant enzyme catalyzes the production of the novel oncometabolite 2- hydroxyglutarate (2-HG). Increased levels of 2-HG inhibits the 2-oxoglutarate dependent dioxygenase class of enzymes in cells that impact a range of cellular functions including chromatin structure and the epigenetic control of gene expression, which are thought to promote tumorigenesis. Because 2-HG is not found at appreciable quantities in normal cells, where basal levels are cleared via 2-HG dehydrogenase, the accumulation to millimolar levels in human gliomas suggests that it could be an ideal biomarker for mutant enzyme activity. Understanding the requirements for mutant IDHI activity in existing tumors, and whether 2- HG levels can serve as a surrogate for mutant enzyme activity in patients are critical issues for the development of new targeted therapies in this disease. In preliminary studies, we and others have characterized the biological correlates and potentially actionable avenues for inducing therapeutic response in IDH mutant gliomas. In Project 3, we will use clinical material to test the hypotheses that non-invasive measurement of 2-HG levels can serve as surrogate for IDH mutant enzyme activity, and that targeting of IDH mutation and 2-HG may be a novel therapeutic strategy for malignant glioma patients. The basic scientist on this project (W Kaelin) is a Howard Hughes Investigator and molecular biologist, and the clinical investigator (DP Cahill) is a practicing neurosurgeon. Dr Kaolin's group helped define the functional metabolic consequences of IDHI mutation and 2-HG production on the epigenome of cancer cells, was the first to show that mutant IDH1 transforms human astrocytes in vitro, and was the first to demonstrate that a potential therapeutic intervention (EglN inhibition) can selectively target the abnormal biochemical environment within 1DH1 mutant tumors. Dr. Cahill's lab performed IDH stratification ofthe recent national RTOG-0525 trial in glioblastoma, and with his colleagues, has established IDHI-mutant orthotopic xenograft glioma models derived from freshly resected patient tumor samples. We believe that the successful execution of Project 3 will support the future development of clinical trials for 1DH1 mutant gliomas.