研究动态
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功能磁共振波谱 (MRS) 在监测癌症中激酶抑制剂反应方面的新作用。

Emerging Role of Functional Magnetic Resonance Spectroscopy (MRS) to Monitor Response to Kinase Inhibitors in Cancer.

发表日期:2024
作者: Kavindra Nath, Pradeep K Gupta, Mariusz A Wasik
来源: Cellular & Molecular Immunology

摘要:

参与信号传导和其他细胞内途径的激酶抑制剂通过提供高度针对性和有效的治疗而彻底改变了癌症治疗。然而,及时监测治疗反应仍然是一个相当大的挑战,因为由于激酶抑制剂的主要细胞抑制作用而不是细胞毒性作用,评估肿瘤体积变化等传统方法无法充分捕捉早期反应或耐药发展。磁共振波谱 (MRS) 是一种非侵入性成像技术,可以通过检测代谢物浓度的变化来深入了解细胞代谢。通过测量代谢物水平,MRS 提供了一种实时评估治疗反应的方法,与传统成像方式相比,可以更早地显示疗效或耐药性。布鲁顿酪氨酸激酶 (BTK) 是参与 B 细胞受体信号传导的关键酶。 BTK 抑制剂已被批准用于治疗套细胞淋巴瘤 (MCL) 和其他 B 细胞恶性肿瘤。最近涉及基因组规模的基因表达、代谢组学和通量组学分析的研究表明,BTK 指标抑制剂依鲁替尼深刻影响 MCL 细胞的关键代谢途径,包括糖酵解、谷氨酰胺分解、戊糖分流、TCA 循环和磷脂代谢。重要的是,依鲁替尼对 MCL 细胞的影响与其对药物的敏感性直接成比例相关。因此,MRS 可非侵入性检测到的特定代谢物浓度的变化(例如分别反映细胞糖酵解和谷氨酰胺分解状态的乳酸和丙氨酸)已成为预测 MCL 细胞对 BTK 抑制的反应和耐药性的潜在生物标志物(均为体外)和体内。验证这些生物标志物在临床环境中的效用的准备工作正在进行中。这些研究可能为监测其他类型癌症中激酶抑制剂的治疗反应铺平道路。
Inhibitors of kinases involved in signaling and other intracellular pathways, have revolutionized cancer treatment by providing highly targeted and effective therapies. However, timely monitoring treatment response remains a considerable challenge since conventional methods such as assessing changes in tumor volume do not adequately capture early responses or resistance development, due to the predominantly cytostatic rather than cytotoxic effect of kinase inhibitors. Magnetic resonance spectroscopy (MRS) is a non-invasive imaging technique that can provide insights into cellular metabolism by detecting changes in metabolite concentrations. By measuring metabolite levels, MRS offers a means to assess treatment response in real-time, providing earlier indications of efficacy or resistance compared to conventional imaging modalities. Bruton's Tyrosine Kinase (BTK) is a critical enzyme involved in B-cell receptor signaling. BTK inhibitors have been approved for the treatment of Mantle Cell Lymphoma (MCL) and other B-cell malignancies. Recent studies involving genome-scale gene expression, metabolomic, and fluxomic analyses have demonstrated that ibrutinib, an index BTK inhibitor, profoundly affects the key metabolic pathways in MCL cells., including glycolysis, glutaminolysis, pentose shunt, TCA cycle and phospholipid metabolism. Importantly, the effects of ibrutinib on MCL cells directly and proportionately correlates with their sensitivity to the drug. Consequently, changes in specific metabolite concentrations detectable non-invasively by MRS such as lactate and alanine reflecting mostly the status of cellular glycolysis and glutaminolysis, respectively, have emerged as potential biomarkers for predicting response and resistance of MCL cells to BTK inhibition, both in vitro and in vivo. Preparations to validate the utility of these biomarkers in clinical setting are under way. These studies may pave the way to monitor therapeutic response to kinase inhibitors also in other types of cancer.