当前位置: X-MOL 学术J. Bone Oncol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma
Journal of Bone Oncology ( IF 3.1 ) Pub Date : 2022-04-16 , DOI: 10.1016/j.jbo.2022.100430
Makoto Nakagawa 1, 2, 3 , Masayuki Yamaguchi 4 , Makoto Endo 2 , Yukino Machida 5 , Ayuna Hattori 3, 6 , Fumie Tanzawa 7 , Shinji Tsutsumi 7 , Issay Kitabayashi 3 , Akira Kawai 1 , Fumihiko Nakatani 1
Affiliation  

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.



中文翻译:

2-羟基戊二酸作为 IDH 突变软骨肉瘤生物标志物的临床应用

背景

软骨肉瘤是一种常见的恶性骨肿瘤,治疗选择有限。大约一半的软骨肉瘤在异柠檬酸脱氢酶 (IDH) 中具有功能获得性突变,突变 IDH 产生 2-羟基戊二酸 (2-HG),这是一种有助于恶性转化的代谢物。因此,抑制 2-HG 的产生是治疗晚期软骨肉瘤的一种新型且有前景的治疗方法。2-HG 也有望成为诊断和治疗 IDH 突变肿瘤的有用生物标志物。然而,很少有研究使用软骨肉瘤临床标本证实了这一点。2-HG 水平的无创监测有助于推断突变 IDH 抑制剂达到治疗目标并确认其在临床实践中的治疗效果。

方法

为了评估 2-HG 作为诊断和治疗效果的替代生物标志物的临床效用,我们使用来自软骨肉瘤患者的冷冻组织和外周血测量了 2-HG 的肿瘤内和血清水平。我们还开发了一种使用磁共振波谱 (MRS)检测体内肿瘤内 2-HG 信号的非侵入性方法

结果

IDH突变肿瘤的瘤内和血清2-HG水平均显着升高,这些水平与生存率降低相关。此外,我们在 IDH 突变软骨肉瘤的异种移植模型中使用 MR 光谱检测到瘤内 2-HG 峰,并观察到在施用突变 IDH1 抑制剂后 2-HG 峰信号消失。

结论

我们的研究结果表明,肿瘤内和血清 2-HG 水平都代表了 IDH 突变肿瘤潜在有用的生物标志物,并且 MR 光谱中的 2-HG 信号具有作为非侵入性生物标志物的潜在价值。总之,这些发现可能对突变 IDH 抑制剂治疗晚期软骨肉瘤的临床开发产生积极影响。

更新日期:2022-04-20
down
wechat
bug