Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target.
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2011-12
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Abstract
Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies.Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth.As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.
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Guo, Changcun, Christopher J Pirozzi, Giselle Y Lopez and Hai Yan (2011). Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target. Current opinion in neurology, 24(6). pp. 648–652. 10.1097/WCO.0b013e32834cd415 Retrieved from https://hdl.handle.net/10161/17846.
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Giselle Yvette López
I am a physician scientist with a clinical focus on neuropathology, and a research interest in brain tumors. Originally from Maryland, I completed my undergraduate training at the University of Maryland, completing degrees in Physiology and Neurobiology as well as Spanish Language and Literature. I subsequently came to Duke for my MD and PhD, and discovered a passion for brain tumor research, and quickly realized that this was my life's calling. Clinically, I specialize in neuropathology. While I have active projects and collaborations on many kinds of brain tumors, my lab's primary focus is oligodendroglioma, a kind of infiltrative brain tumor that impacts adults. Our goal is to identify new ways to treat these tumors and improve the lives of patients with oligodendrogliomas and other kinds of brain tumors. By blending together computational approaches with wet lab approaches, we use the strengths inherent in different research modalities to excel in identifying unexplored pathways and thinking outside the box to identify new ways to target this brain tumor. We do this through research in an inclusive, multidisciplinary lab environment that strives for excellence in research while creating well-rounded, thriving scientists ready for the next step in their careers.
Research Opportunities
We currently have opportunities in the laboratory for one-year projects (ideal for post-bac fellows or third year med student research experiences). These projects are centered on identifying and testing novel therapeutic approaches for oligodendroglioma using in vitro and in vivo model systems. Please reach out if you are interested and would like to hear more about my mentoring philosophy, lab culture, and opportunities to be at the cutting edge of science.
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