Treatment response assessment in IDH-mutant glioma patients by noninvasive 3D functional spectroscopic mapping of 2-hydroxyglutarate

Ovidiu C. Andronesi, Franziska Loebel, Wolfgang Bogner, Małgorzata Marjańska, Matthew G.Vander Heiden, A. John Iafrate, Jorg Dietrich, Tracy T. Batchelor, Elizabeth R. Gerstner, William G. Kaelin, Andrew S. Chi, Bruce R. Rosen, Daniel P. Cahill

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Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. Experimental Design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median=48.1%; 95% confidence interval=27.3%-56.5%; P=0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R2=0.88, P=0.002) with clinical status evaluated by KPS. Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging maybe used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas.

Original languageEnglish (US)
Pages (from-to)1632-1641
Number of pages10
JournalClinical Cancer Research
Issue number7
StatePublished - Apr 1 2016

Bibliographical note

Funding Information:
This work was supported by NCI/NIH K22 Career Award 1K22CA178269-01 (to O.C. Andronesi); Burroughs-Wellcome Career Award, DFHCC/MIT Koch Institute Bridge Foundation and NIH Brain Cancer SPORE (to D.P. Cahill); NIH R01CA129371 and K24CA125440A (to T.T. Batchelor); Austrian Science Fund (FWF) KLI-61 (toW. Bogner); Biotechnology Research Center (BTRC) grant P41 RR008079 and P41 EB015894 (NIBIB), and NCC P30 NS057091 (M. Marja?ska); NIH S10RR013026, S10RR021110, S10RR023401 (to B. Rosen).

Publisher Copyright:
© 2015 American Association for Cancer Research.


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