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

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.

• Authors: Makoto Nakagawa, Masayuki Yamaguchi, Makoto Endo, Yukino Machida, Ayuna Hattori, Fumie Tanzawa, Shinji Tsutsumi, Issay Kitabayashi, Akira Kawai, Fumihiko Nakatani
• Journal: Journal of bone oncology (J Bone Oncol) Vol. 34 Pg. 100430 (Jun 2022) ISSN: 2212-1366 [Print] Netherlands
• PMID: 35493690 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Published by Elsevier GmbH.