New Discovery in Brain Tumors and Applications of Magnetic Resonance Technology

  • Posted on: Thu, 08/27/2015 - 23:11
  • By: OCHIS
Abstract: 
Our understanding of tumorigenesis and knowledge of neuro-oncology have been improved dramatically by the finding of mutations including isocitrate dehydrogenase (IDH) enzymes. IDH converts isocitrate into a-ketoglutarate (aKG) in cytosol (IDH1) and mitochondria (IDH2). In 2009, Yan et al identified the mutations of IDH1 and IDH2 in 60~90% of World Health Organization (WHO) grade II and III gliomas and secondary glioblastoma (grade IV).


New Dicovery In Brian Tumors - Isocitrate Dehydrogenase Mutations

Our understanding of tumorigenesis and knowledge of neuro-oncology have been improved dramatically by the finding of mutations including isocitrate dehydrogenase (IDH) enzymes. IDH converts isocitrate into a-ketoglutarate (aKG) in cytosol (IDH1) and mitochondria (IDH2). In 2009, Yan et al identified the mutations of IDH1 and IDH2 in 60~90% of World Health Organization (WHO) grade II and III gliomas and secondary glioblastoma (grade IV) [1].

Mutated Gliomas

IDH mutated gliomas result in overall significantly higher survival rate [1-3] and better response to chemotherapy than IDH wild type brain tumors [4]. As mentioned above, IDH mutations are restriced to certain types of tumor and are absent in primary glioblastoma and grade I benign tumors. IDH mutations happen in the early stage of the tumorigenesis and thought to be the initiating mutation in the tumor[5]. Similarly, IDH mutations were found in cytogenetically normal subtypes of acute myelogenous leukemia (AML) and small number of prostate cancer [6].

It caught researcher's attention that IDH mutations has another function of converting aKG into an oncometabolite 2-hydroxyglutarate (2HG) [7]. The accumulation of 2HG can affect the function of aKG related process and thus may serve as a facilitator of further oncogenic change [8-10].

IDH inhibitor

A series of IDH inhibitor drugs have been developed and clinical trials on these drugs for IDH mutated glioma and AML patients have been started[11-17]. Following the treatment with drug AGI-5198 [11], reduction in tumor volume and 2HG level were observed. Reduction of 2HG was also found with AGI-6780 drug [14] in AML with change in cell differetiation. Besides, there are several other groups work on developing new drug and theraputic methods targeting IDH mutated tumors.

More importantly, 2HG accumulation in IDH mutated gliomas can increase by 100-1000 fold and thus reaching milli-molar level [7]. This is within a well detectable range of in vivo non-invasive Magnetic Resonance Spectroscopy.

In vivo Magnetic Resonance Spectroscopy

In vivo Magnetic Resonance Spectroscopy (MRS) is a non-invasive tool to quantify metabolites in the human body using Magnetic Resonance Imaging (MRI) scanner. 1H MRS is available in every human body MRI facilities.

Insteated of looking at proton signals from water by MRI, MRS focuses on proton signals from other metabolite including Lipid, Choline, Creatine, Glutamate and Glutamine etc [18]. In the human brain, in vivo 1H MRS is capable of detecting more than 20 metabolites [18].

However, due to the similarity of the proton signals from different metabolites, a causious engineering work (modeling and simulation) has to be done to best differentiate each metabolites signals from severely overlapped spectrum [19].

Several techniques have been published to measure 2HG in IDH mutated gliomas [19-21]. As MRS Imaging (MRSI) technique is widely available, reliable mapping of 2HG in the entire brain is possible [19]. Both MRS and MRSI give a huge potential in drug development including IDH mutations related trials without invasively monitoring metabolites with brain biopsy.

References

[1] Yan H, et al. IDH1 and IDh2 mutations in gliomas. E Engl J Med. 2009;360(8):765-773.

[2] Leu S, et al. IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro Oncol. 2013;15(4):469-479.

[3] Metellus P, et al. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol. 2010;120(6):719-729.

[4] Houillier C, et al. IDH1 or IDH2 mutations predict longer survival and reponse to temozolomide in low-grade gliomas. Neurology. 2010;75(17):1560-1566.

[5] Juratli TA, et al. IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J Neurooncol. 2012;108(3):403-410.

Author's Biography

Zhongxu An

is a Ph.D. candidate at the University of Texas Southwestern Medical Center and works as a research assistant in the Advanced Imaging Research Center under the guidance of Dr. Changho Choi. He is dedicated in in-vivo Magnetic Resonance Spectroscopy and Spectroscopy Imaging research in brain tumors at 3T and 7T.

Email: Zhongxu.An@utsouthwestern.edu