Gliomas, the most common types of brain tumor, are also among the most lethal of cancers: Their mortality rate is almost 100%, partly because few treatments exist. A team of researchers from the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA), Harvard University (Cambridge, MA, USA), Massachusetts General Hospital (MGH; Boston, MA, USA) and Agios Pharmaceuticals (Cambridge, MA, USA) has now developed a way to identify a particular subset of brain tumors, which may help physicians choose treatments and create new drugs that target the disease’s underlying genetic mutation.

Scientists have known for some time that many brain tumors involve a mutation in the gene for an enzyme called isocitrate dehydrogenase (IDH). This enzyme is involved in cell metabolism--the process of breaking down glucose molecules to extract energy from them. IDH mutations are found in up to 86% of low-grade gliomas, which have a better prognosis than high-grade gliomas, also called glioblastomas. Patients with low-grade gliomas can survive for years, although the tumors nearly always prove fatal.

Several pharmaceutical companies are now pursuing drugs that target IDH, in hopes of halting tumor growth. Some of those agents may enter clinical trials within the year, reported Dr. Matthew Vander Heiden, a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

Dr. Vander Heiden is part of the team that developed imaging technology to reveal whether brain tumors have the IDH mutation, which could help researchers track whether potential drugs are having the desired effect. The researchers described their technique in the January 11, 2012, online edition of the journal Science Translational Medicine.

When IDH is mutated, a tumor cell begins to generate mass quantities of a molecule called 2-hydroxyglutarate (2-HG). Earlier studies had revealed that 2-HG interferes with the regulation of DNA expression, causing the cell to regress to an immature state conducive to uncontrolled growth. IDH mutations are also found in some forms of leukemia, and rarely, in other cancers.

The new imaging technique uses magnetic resonance (MR) spectroscopy, which analyzes the magnetic properties of atomic nuclei, to locate 2-HG in the brain. Other researchers have tried to image 2-HG with MR spectroscopy, but found it difficult to differentiate 2-HG from some of the brain’s common metabolites, such as glutamate and glutamine.

MGH researchers led by Dr. Greg Sorensen and Dr. Ovidiu Andronesi, the lead author of the article, found an unequivocal way to identify 2-HG by doing the MR scans in two dimensions, which provides enough data to distinguish conclusively 2-HG from similar compounds. The imaging technique does not require any specialized equipment; it can be performed with the clinical MRI scanners already found in most hospitals.

“The most exciting thing about this is it opens up the possibility that as drugs against gliomas come online, you could know which patients with brain tumors to put in the clinical trials, and you would know if the drug you’re giving them is actually doing what it’s supposed to do,” stated Vander Heiden, a professor of biology at MIT.

Presently, the only way to measure 2-HG levels is by taking a brain biopsy and performing mass spectrometry on the tissue. This is typically done when a brain tumor is first diagnosed, but cannot be done on a regular basis, reported Dr. Hai Yan, an assistant professor of pathology at Duke University (Durham, NC, USA). “If you can detect [2-HG] in the tissue or blood, it would allow physicians to tell if treatments for the tumor have been effective or not,” said Dr. Yan, who was not involved in this study.

Related Links:
Massachusetts Institute of Technology
Harvard University
Agios Pharmaceuticals