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.
Bibliographical noteFunding 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).