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

Makoto Nakagawa, Masayuki Yamaguchi, Makoto Endo, Yukino Machida, Ayuna Hattori, Fumie Tanzawa, Shinji Tsutsumi, Issay Kitabayashi, Akira Kawai, Fumihiko Nakatani

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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. Methods: 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) Results: 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. Conclusions: 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.

Original languageEnglish
Article number100430
JournalJournal of Bone Oncology
Volume34
DOIs
Publication statusPublished - Jun 2022

All Science Journal Classification (ASJC) codes

  • Oncology

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