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A Novel Target for Glioblastoma Therapy

A genomewide mutational analysis might pave the way to personalizing brain tumor treatments based on molecular subtypes.

Classification of cancers is rapidly changing with advances in genomewide studies of glioblastomas (GBMs; Nature 2008; 455:1061). Researchers previously found somatic mutations in the gene for isocitrate dehydrogenase 1 (IDH1) in 83% of secondary GBMs (arising from lower-grade gliomas) but in only 7% of primary GBMs (arising de novo) (Science 2008; 321:1807).

The researchers conducted a follow-up study of IDH genes in a larger dataset of 445 CNS and 494 non-CNS tumors. They screened for mutations in IDH1 and (in tumors without IDH1 mutations) in IDH2. Only glial tumors had mutations. Most (>70%) of the grade II and III gliomas and secondary GBMs had mutations in either IDH1 (in the R132 residue) or IDH2 (in the R172 residue). Analysis in transfected cells showed that these mutations reduced enzymatic activity of the encoded proteins. Among the patients with glioblastomas or anaplastic astrocytomas, those with the mutations had better survival than those without.

Comment: This study highlights the value of genomewide approaches to understanding cancer pathogenesis. The finding of ubiquitous mutations in IDH genes in grade II and III gliomas and in secondary GBMs implicates these mutations in the pathogenesis of this subset of gliomas. Furthermore, given the heterogeneous nature of GBMs, these mutations can be used to subclassify tumors for diagnostic purposes. The implication is that the underlying genetics may determine responsiveness to treatments and thus allow us to personalize therapy.

Another study validated the relevance of the current findings: Researchers showed that the mutation in IDH1 causes reduced levels of -ketoglutarate, producing an increase in hypoxia-inducible factor subunit HIF-1. The resulting increase in the supply of nutrients and oxygen to tumor cells leads to tumor growth (Science 2009; 324:261). An -ketoglutarate derivative reversed the effect of the IDH1 mutation. This finding opens the possibility of developing a clinical drug for patients harboring these mutations. As these studies highlight, the reality of personalized therapy based on molecular classification is on the horizon.

— Santosh Kesari, MD, PhD

Dr. Kesari is Assistant Professor in Neurology, Harvard Medical School; Associate Neurologist, Department of Neurology, Brigham and Women's Hospital; and Associate Neuro-Oncologist, Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston.

Published in Journal Watch Neurology June 2, 2009

Citation(s):

Yan H et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009 Feb 19; 360:765.

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