Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma

• Published in: Journal of bone oncology Vol. 34; p. 100430
• Main Authors: Nakagawa, Makoto, Yamaguchi, Masayuki, Endo, Makoto, Machida, Yukino, Hattori, Ayuna, Tanzawa, Fumie, Tsutsumi, Shinji, Kitabayashi, Issay, Kawai, Akira, Nakatani, Fumihiko
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier GmbH 01.06.2022; Elsevier
• Subjects: 2-Hydroxyglutarate (2-HG); Biomarker; Chondrosarcoma; isocitrate dehydrogenase (IDH); Research Paper; AML; Chondrosarcoma; Biomarker; MR; MRI; isocitrate dehydrogenase (IDH); NOD-SCID; STEAM; 2-Hydroxyglutarate (2-HG); IDH; ROI; 2-HG; MRS; NMR; NOD-SCID, NOD/ShiJic-scidJcl; AML, acute myeloid leukemia; IDH, isocitrate dehydrogenase; MR, magnetic resonance; MRI, magnetic resonance imaging; ROI, region of interest; NMR, nuclear magnetic resonance; 2-HG, 2-hydroxyglutarate; MRS, magnetic resonance spectroscopy; STEAM, stimulated echo acquisition mode
• ISSN: 2212-1374; 2212-1366; 2212-1374
• DOI: 10.1016/j.jbo.2022.100430

•2-HG is expected to be a useful biomarker for diagnosing and treating IDH-mutant tumors.•Both intratumoral and serum levels of 2-HG were significantly higher in IDH-mutant tumors.•Serum 2-HG levels were correlated with tumor volume and tumor progression.•MR spectroscopy (MRS) detected 2-HG peaks in a xenograft model of IDH-mutant chondrosarcoma.•In vivo MRS can be a useful tool for determining the therapeutic effect of mutant IDH inhibitors. Chondrosarcoma is a common form of malignant bone tumor with limited treatment options. Approximately half of chondrosarcomas harbor gain-of-function mutations in isocitrate dehydrogenase (IDH), and mutant IDH produces 2-hydroxyglutarate (2-HG), which is an oncometabolite that contributes to malignant transformation. Therefore, inhibiting 2-HG production is a novel and promising treatment for advanced chondrosarcoma. 2-HG is also expected to be a useful biomarker for the diagnosis and treatment of IDH-mutant tumors. However, few studies have confirmed this using chondrosarcoma clinical specimens. Non-invasive monitoring of 2-HG levels is useful to infer that mutant IDH inhibitors reach therapeutic targets and to confirm their therapeutic efficacy in clinical practice. To evaluate the clinical utility of 2-HG as a surrogate biomarker for diagnosis and therapeutic efficacy, we measured intra-tumor and serum levels of 2-HG using frozen tissues and peripheral blood from patients with chondrosarcoma. We also developed a non-invasive method to detect intra-tumor 2-HG signals in vivo using magnetic resonance spectroscopy (MRS) Both intratumoral and serum 2-HG levels were significantly elevated in IDH-mutant tumors, and these levels correlated with decreased survival. Furthermore, we detected intratumoral 2-HG peaks using MR spectroscopy in a xenograft model of IDH-mutant chondrosarcoma, and observed that 2-HG peak signals disappeared after administering an inhibitor of mutant IDH1. Our findings suggest that both intratumoral and serum 2-HG levels represent potentially useful biomarkers for IDH-mutant tumors and that the 2-HG signal in MR spectra has potential value as a non-invasive biomarker. Taken together, these findings may positively impact the clinical development of mutant IDH inhibitors for the treatment of advanced chondrosarcoma.