An MR spectroscopic imaging technique has the potential to predict the prognosis and response to treatment of patients with low-grade infiltrating gliomas that harbor mutations in the gene encoding isocitrate dehydrogenase 1, according to ex vivo and in vivo imaging studies.
The approach takes advantage of experimental results that show the production and accumulation of 2-hydroxyglutarate (2HG) is a consequence of new enzymatic activity of mutant IDH1 variants that are present in more than 70% of patients with low-grade gliomas and have a better than 5-year survival rate than do wild-type IDH1 gliomas. The metabolite is found in a high enough concentration for new MR spectroscopic methods to differentiate it in vivo from the overlapping spectra of metabolites with similar chemical shifts.
Patrick Y. Wen
The studies suggest great potential for such imaging tests if the biological rationale for such an approach can be verified in animal studies and much larger validation studies, Dr. Patrick Y. Wen said in an interview.
"Being able to measure 2HG in patients noninvasively with MR spectroscopy opens up a whole lot of options. You could diagnose patients. It would help in the diagnosis of the tumor itself, and it would give you an idea of the type of tumor and the prognosis. There are also companies making drugs against IDH, and so you could now noninvasively identify those patients who would be suitable for these drugs," said Dr. Wen, director of the division of neuro-oncology at Brigham and Women’s Hospital, Boston. He was not involved in the studies.
In one study, Adam Elkhaled and his colleagues at the University of California, San Francisco, examined 104 tissue samples from 52 patients who had previously been diagnosed with World Health Organization grade II glioma but were presenting for surgical resection because of suspected disease recurrence (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002796]).
They used proton high-resolution magic angle spinning nuclear MR spectroscopy to evaluate the samples for the presence of 2HG. Spectra were positive for 2HG in 33 of 38 patients with evaluable samples (58 of 66 tissue specimens), which translated to a concordance of 86% between the presence of 2HG in tissue samples (51 of 59) and positive IDH1 mutation status (32 of 38).
The investigators found positive correlations in the tissue specimens between 2HG levels and other metabolites that are commonly associated with tumor, as well as with common findings in tumor tissue histopathology, such as mitotic activity, relative tumor content, and cellular density, which "implies that in vivo levels of 2HG may be able to contribute not only to the classification of glioma but also to characterizing the spatial extent of infiltrative lesions," Mr. Elkhaled and his colleagues wrote. The results also suggest that the presence of 2HG may help in "determining the extent of recurrent tumor in an in vivo setting," especially when differentiating tumor from treatment effects.
Dr. Ovidiu C. Andronesi of Massachusetts General Hospital, Boston, and colleagues took these ex vivo findings a step further by applying a two-dimensional correlation MR spectroscopy technique that is able to resolve 2HG from similar metabolites, such as glutamate and glutamine (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002693]).
In a preliminary study, they applied the technique to determine the presence of 2HG and measure its level relative to the amounts of glutamate and glutamine present in vivo in two glioma patients with an IDH1 mutation and eight control patients with wild-type IDH1 (including four with primary glioblastoma and four healthy volunteers). The two-dimensional technique correctly identified 2HG in the two patients with IDH1 mutations and did not find 2HG – as expected – in the patients with wild-type IDH1.
Pharmaceutical companies are interested in developing inhibitors of mutated IDH1, Dr. Andronesi and his associates noted, because 2HG might act as an oncometabolite that competitively inhibits enzymes involved in altering histone proteins and DNA methylation, as well as enzymes that affect the level of hypoxia-inducible factor 1, which may be involved in tumor angiogenesis and growth.
Many patients’ low-grade gliomas eventually recur, but not all will get another biopsy, which is where Dr. Wen thought the ability to monitor 2HG levels noninvasively would be of value, particularly in measuring its levels in patients taking inhibitors of mutant IDH. He noted that falling 2HG levels in these patients could be a biomarker response, which "opens up a whole number of options that have never previously been possible in brain tumors because we haven’t had such a biomarker before."
Both studies were funded by grants from the National Institutes of Health. Dr. Andronesi also received support from the Harvard Catalyst (the Harvard Clinical and Translational Science Center).