Ruiz-Rodado Victor, Dowdy Tyrone, Lita Adrian, Kramp Tamalee, Zhang Meili, Shuboni-Mulligan Dorela, Herold-Mende Christel, Armstrong Terri S, Gilbert Mark R, Camphausen Kevin, Larion Mioara
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States.
Front Oncol. 2022 Oct 24;12:979537. doi: 10.3389/fonc.2022.979537. eCollection 2022.
Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based C-tracing experiments were performed at end-point utilizing [U-C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws.
星形细胞瘤是最常见的脑肿瘤亚型，目前尚无治愈性治疗方法。对患者进行纵向评估，通常是磁共振成像（MRI），至关重要，因为肿瘤进展可能比临床进展更早出现。MRI通常提供了监测疾病的手段，但它仅能告知肿瘤的结构变化，而分子变化可能作为治疗反应发生，而无任何MRI可见的变化。放射治疗（RT）在手术后作为星形细胞瘤标准治疗的一部分常规进行，标准治疗还可能包括使用替莫唑胺的化疗。监测对RT的反应是患者管理的关键因素。在此，我们在接受放射治疗的星形细胞瘤小鼠模型中提供了治疗反应的血浆和组织代谢生物标志物。通过液相色谱质谱联用（LC/MS）随时间获取的血浆代谢谱进行了多变量经验贝叶斯时间序列分析（MEBA）和包括随机森林作为分类策略的受试者工作特征（ROC）评估。这些分析揭示了与对照组相比接受放射治疗的小鼠血浆代谢组的变化；具体而言，富马酸盐是最佳鉴别特征。此外，在终点利用[U-C]-谷氨酰胺进行了基于核磁共振（NMR）的C追踪实验，以研究其在肿瘤和对侧组织中的命运。照射小鼠的肿瘤组织中糖酵解代谢物（如磷酸烯醇丙酮酸）水平较低，并且在放疗组中观察到谷氨酰胺向琥珀酸的通量更高。本文提供的血浆生物标志物可在临床中得到验证，从而改善整个放疗过程中脑肿瘤患者的评估。此外，肿瘤组织中与放疗相关的代谢重编程可能导致使用抽血监测治疗的潜在代谢成像方法。
