Hyperpolarized 13C MRSI Monitoring of Pyruvate Metabolism to Assess Drug Action

在美国，每年大约有17,000例新的恶性脑癌被诊断出来。 即使接受手术切除、放疗和化疗，胶质母细胞瘤(GBM)患者中 难治性疾病，通常在确诊后2年内死亡。一个主要的限制 在对复发的GBM进行有效治疗的开发中，缺乏一种可靠的方法来预测早期 对治疗的反应。使用常规磁共振(MR)成像来监测反应通常 不可靠，往往无法区分治疗效果和肿瘤反应。在动物模型中 我们最近发现替莫唑胺(TMZ)和Pisk途径抑制剂的反应是相关的。 随着超极化碳13(130)丙酮酸转化为13C乳酸的肿瘤特异性降低 无创130磁共振波谱成像(MRSI)可检测到超极化比率的下降 乳酸到丙酮酸(Lac/PYR)。因此，我们假设Lac/PYR的测量可以作为早期的 TMZ、PI3K抑制剂和潜在的一系列药物治疗后患者的药物作用指标 其他特工。这一假设将通过1)定义体外敏感性并验证靶向抑制来检验 复发性人GBM细胞暴露于TMZ和其他新型靶向药物，包括XL765和SAHA2) 确定药物对药物中130丙酮酸转化为130乳酸的影响 敏感/耐药的成对GBM细胞，并将这些变化与靶向抑制和药物敏感性联系起来，3) 确定药物诱导的~(13)C丙酮酸向~(130)乳酸转化是否平行靶标 体外的抑制和药物敏感性在体内的异种移植中也是如此，以及4)确定治疗是否诱导 超极化130MRSI检测到的丙酮酸代谢的改变可以单独使用，也可以用于 与其他影像标志物联合作为临床靶点抑制和早期反应的生物标志物 对复发的基底膜患者的试验。与项目1密切互动，所有共享资源核心将 这对成功开展拟议的研究至关重要。

Approximately 17,000 new cases of malignant brain cancer are diagnosed per year in the United States. Even with surgical resection, radiation, and chemotherapy, patients with glioblastoma (GBM), the most refractory form of the disease, typically succumb to the disease within 2 years of diagnosis. A major limitation in the development of effective therapies for recurrent GBM is the lack of a reliable method to predict early response to therapy. Monitoring response using conventional magnetic resonance (MR) imaging is often unreliable and are often unable to distinguish treatment effects from tumor response. In animal models of GBM, we recently found that response to temozolomide (TMZ) and PISK pathway inhibitors is associated with a tumor-specific decrease in the conversion of hyperpolarized carbon 13 (130) pyruvate to 13C lactate detectable by non invasive 130 MR spectroscopic imaging (MRSI) as a drop in the ratio of hyperpolarized lactate to pyruvate (Lac/Pyr). We therefore hypothesize that measurement of Lac/Pyr could serve as an early indicator of drug action in patients following treatment with TMZ, PI3K inhibitors, and potentially a range of other agents. This hypothesis will be tested by 1) defining in vitro sensitivity and verifying target inhibition in recurrent human GBM cells exposed to TMZ and other novel targeted agents including XL765 and SAHA 2) defining the effect of the drugs on the conversion of 130 pyruvate to 130 lactate in the drug sensitive/resistant paired GBM cells, and relating these changes to target inhibition and drug sensitivity, 3) determining if the drug-induced changes in 13C pyruvate to 130 lactate conversion that parallel target inhibition and drug sensitivity in vitro also do so in xenografts in vivo, and 4) determining if treatment-induced alterations in pyruvate metabolism detected by hyperpolarized 130 MRSI can be used alone, or in combination with other imaging markers, as a biomarker of target inhibition and early response in clinical trials of recurrent GBM patients. Close interactions with Project 1 and all the Shared Resource Cores will be critical to the successful conduct of the proposed studies.