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

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 contribute...

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Autores principales: Nakagawa, Makoto, Yamaguchi, Masayuki, Endo, Makoto, Machida, Yukino, Hattori, Ayuna, Tanzawa, Fumie, Tsutsumi, Shinji, Kitabayashi, Issay, Kawai, Akira, Nakatani, Fumihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048072/
https://www.ncbi.nlm.nih.gov/pubmed/35493690
http://dx.doi.org/10.1016/j.jbo.2022.100430
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author Nakagawa, Makoto
Yamaguchi, Masayuki
Endo, Makoto
Machida, Yukino
Hattori, Ayuna
Tanzawa, Fumie
Tsutsumi, Shinji
Kitabayashi, Issay
Kawai, Akira
Nakatani, Fumihiko
author_facet Nakagawa, Makoto
Yamaguchi, Masayuki
Endo, Makoto
Machida, Yukino
Hattori, Ayuna
Tanzawa, Fumie
Tsutsumi, Shinji
Kitabayashi, Issay
Kawai, Akira
Nakatani, Fumihiko
author_sort Nakagawa, Makoto
collection PubMed
description 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.
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spelling pubmed-90480722022-04-29 Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma Nakagawa, Makoto Yamaguchi, Masayuki Endo, Makoto Machida, Yukino Hattori, Ayuna Tanzawa, Fumie Tsutsumi, Shinji Kitabayashi, Issay Kawai, Akira Nakatani, Fumihiko J Bone Oncol Research Paper 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. Elsevier 2022-04-16 /pmc/articles/PMC9048072/ /pubmed/35493690 http://dx.doi.org/10.1016/j.jbo.2022.100430 Text en © 2022 The Authors. Published by Elsevier GmbH. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Nakagawa, Makoto
Yamaguchi, Masayuki
Endo, Makoto
Machida, Yukino
Hattori, Ayuna
Tanzawa, Fumie
Tsutsumi, Shinji
Kitabayashi, Issay
Kawai, Akira
Nakatani, Fumihiko
Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma
title Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma
title_full Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma
title_fullStr Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma
title_full_unstemmed Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma
title_short Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma
title_sort clinical usefulness of 2-hydroxyglutarate as a biomarker in idh-mutant chondrosarcoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048072/
https://www.ncbi.nlm.nih.gov/pubmed/35493690
http://dx.doi.org/10.1016/j.jbo.2022.100430
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