Department of Radiology and Biomedical Imaging, University of California San Francisco, 1700 4th Street Box 2532, San Francisco, CA 94158, USA.
Neuroimage. 2012 Jan 2;59(1):193-201. doi: 10.1016/j.neuroimage.2011.07.034. Epub 2011 Jul 23.
Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in humans. Because the phosphatidylinositol-3-kinase (PI3K) signaling pathway is activated in more than 88% of GBM, new drugs which target this pathway, such as the mTOR inhibitor Everolimus, are currently in clinical trials. Early tumor response to molecularly targeted treatments remains challenging to assess non-invasively, because it is often associated with tumor stasis or slower tumor growth. Innovative neuroimaging methods are therefore critically needed to provide metabolic or functional information that is indicative of targeted therapeutic action at early time points during the course of treatment. In this study, we demonstrated for the first time that hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) can be used on a clinical MR system to monitor early metabolic response of orthotopic GBM tumors to Everolimus treatment through measurement of the HP lactate-to-pyruvate ratios. The study was performed on a highly invasive non-enhancing orthotopic GBM tumor model in rats (GS-2 tumors), which replicates many fundamental features of human GBM tumors. Seven days after initiation of treatment there was a significant drop in the HP lactate-to-pyruvate ratio from the tumor tissue in treated animals relative to day 0 (67%±27% decrease). In the control group, no significant changes in the HP lactate-to-pyruvate ratios were observed. Importantly, at the 7 day time point, conventional MR imaging (MRI) was unable to detect a significant difference in tumor size between control and treated groups. Inhibition of tumor growth by conventional MRI was observed from day 15 of treatment. This implies that the decrease in the HP lactate-to-pyruvate ratio could be detected before any treatment-induced inhibition of tumor growth. Using immunohistochemical staining to further examine tumor response to treatment, we found that the decrease in the HP lactate-to-pyruvate ratio was associated with a drop in expression of lactate dehydrogenase, the enzyme that catalyzes pyruvate to lactate conversion. Also evident was decreased staining for carbonic anhydrase IX (CA-IX), an indicator of hypoxia-inducible factor 1α (HIF-1α) activity, which, in turn, regulates expression of lactate dehydrogenase. To our knowledge, this study is the first report of the use of HP 13C MRSI at a clinical field strength to monitor GBM response to molecularly targeted treatments. It highlights the potential of HP lactate-to-pyruvate ratio as an early biomarker of response, thereby supporting further investigation of this non-invasive imaging approach for eventual clinical application.
胶质母细胞瘤（GBM）是人类最常见和致命的原发性恶性脑肿瘤。由于磷脂酰肌醇-3-激酶（PI3K）信号通路在超过 88%的 GBM 中被激活，因此目前正在临床试验中针对该通路的新药，如 mTOR 抑制剂依维莫司。早期肿瘤对分子靶向治疗的反应仍然难以进行非侵入性评估，因为它通常与肿瘤停滞或肿瘤生长缓慢有关。因此，迫切需要创新的神经影像学方法来提供代谢或功能信息，以指示治疗过程中早期治疗的靶向治疗作用。在这项研究中，我们首次证明，通过测量 HP 乳酸与丙酮酸的比率，超极化（HP）13C 磁共振波谱成像（MRSI）可用于临床磁共振系统来监测原位 GBM 肿瘤对依维莫司治疗的早期代谢反应。该研究在大鼠（GS-2 肿瘤）中进行了侵袭性非增强性原位 GBM 肿瘤模型，该模型复制了许多人类 GBM 肿瘤的基本特征。在治疗后 7 天，与第 0 天（67%±27%减少）相比，治疗动物的肿瘤组织中 HP 乳酸与丙酮酸的比率显着下降。在对照组中，没有观察到 HP 乳酸与丙酮酸比率的显着变化。重要的是，在 7 天时间点，常规磁共振成像（MRI）无法检测到对照组和治疗组之间肿瘤大小的显着差异。从治疗的第 15 天开始观察到肿瘤生长的抑制。这意味着可以在任何治疗引起的肿瘤生长抑制之前检测到 HP 乳酸与丙酮酸比率的降低。通过免疫组织化学染色进一步检查肿瘤对治疗的反应，我们发现 HP 乳酸与丙酮酸比率的降低与乳酸脱氢酶表达的降低有关，乳酸脱氢酶是催化丙酮酸转化为乳酸的酶。还明显减少了碳酸酐酶 IX（CA-IX）的染色，CA-IX 是缺氧诱导因子 1α（HIF-1α）活性的指标，反过来又调节乳酸脱氢酶的表达。据我们所知，这项研究是首次在临床场强下使用 HP 13C MRSI 监测 GBM 对分子靶向治疗的反应。它突出了 HP 乳酸与丙酮酸比率作为早期反应生物标志物的潜力，从而支持对这种非侵入性成像方法进行进一步研究，以期最终用于临床应用。
