Gliomas are the most common primary central nervous system tumor but the molecular mechanisms responsible for the development and progression of these tumors are far from being completely understood. Recently, high-throughput sequencing of grade IV glioblastoma multiforme (GBM) tumors identified a novel mutation in isocitrate dehydrogenase 1 (IDH1) in 12% of the samples analyzed. Further studies have found this mutation to be present in ~80% of grade II-III gliomas and secondary GBM. This mutation has never before been linked to cancer and the function remains unclear. This residue is located in the active site of the enzyme and is critical for isocitrate binding. IDH proteins generate reduced NADPH from NADP+ by catalyzing the oxidative decarboxylation of isocitrate to 1-ketoglutarate (1-KG). The mutant protein has been suggested to function as a tumor suppressor due to its impaired enzymatic activity. Prolylhydroxylases, which hydroxylate and induce the degradation of hypoxia-inducible factor 11 (HIF-11), require 1-KG;therefore, decreased IDH activity may stabilize HIF-11. Activation of this pathway leads to the induction of HIF-1 target genes that affect angiogenesis, metabolism, growth and differentiation, apoptosis and autophagy, as well as cell motility. However, IDH mutations are heterozygous suggesting that these mutations may be gain of function with oncogenic potential rather than loss-of-function. In vitro studies have shown that the mutated IDH1 protein takes on a new function: converting 1-KG to R(-)-2-hydroxyglutarate (2-HG) and consuming NADPH. This is supported by findings that 2-HG levels are elevated in gliomas containing an IDH1 mutation. Furthermore, accumulation of 2-HG in the brain is associated with an increased risk of developing brain tumors. The net result of either process is reduced 1-KG and NADPH, which is an important cofactor necessary to maintain normal levels of reduced glutathione to combat reactive oxygen species (ROS). Under these conditions, cells may continually accumulate ROS-induced oxidative DNA damage and increasing numbers of mutations, which can drive malignant transformation. Interestingly, the presence of an IDH mutation is an independent marker for positive prognosis. The objective of this study is to define the role of IDH mutations in glioma formation, maintenance, and response to therapy. We hypothesize that mutations in IDH contribute to glioma formation, are required for tumor maintenance, and sensitize the tumor cells to conventional therapies. To test this hypothesis we will use a well established glioma model system to determine if expression of mutant IDH confers a growth advantage to astrocytes in vitro, plays a role in the development and maintenance of gliomas in vivo, and influences response to therapy. A better understanding of the role(s) of mutant IDH in the biology of these gliomas will guide the development of new therapies to improve survival and reduce morbidity in these patients.

Public Health Relevance

Diffuse gliomas are the most common primary brain tumor in adults and are associated with a poor prognosis. This study aims to further our understanding of the functions of mutant isocitrate dehydrogenase (IDH), which has recently been identified in a significant percentage of these brain tumors. A better understanding of the contribution of IDH to the formation and maintenance of these tumors will guide the development of new therapies to improve survival and reduce morbidity in glioma patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075155-03
Application #
8259742
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Fountain, Jane W
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$327,031
Indirect Cost
$108,281
Name
University of Utah
Department
Surgery
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Cohen, Adam L; Holmen, Sheri L; Colman, Howard (2013) IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep 13:345