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

在美国，每年大约有17，000例新的恶性脑癌病例被诊断出来。 即使手术切除，放疗和化疗，胶质母细胞瘤（GBM）患者， 疾病的难治性形式，通常在诊断后2年内死于疾病。一个主要限制 在复发性GBM的有效治疗方法的发展中，缺乏一种可靠的方法来预测早期GBM的发生， 对治疗的反应。使用常规磁共振（MR）成像监测响应通常是不可能的。 不可靠，并且通常无法区分治疗效果与肿瘤反应。的动物模型中 GBM，我们最近发现对替莫唑胺（TMZ）和PISK通路抑制剂的反应与 在超极化碳13（130）丙酮酸向13 C乳酸的转化中具有肿瘤特异性降低 通过非侵入性130 MR光谱成像（MRSI）可检测为超极化率的下降， 乳酸转化为丙酮酸（Lac/Pyr）。因此，我们假设Lac/Pyr的测量可以作为早期的 TMZ、PI 3 K抑制剂和可能的一系列药物治疗后患者的药物作用指标 其他代理人。该假设将通过以下方式进行检验：1）定义体外敏感性并验证靶点抑制作用 暴露于TMZ和其他新型靶向药物（包括XL 765和SAHA）的复发性人GBM细胞2） 确定药物对药物中130丙酮酸转化为130乳酸的作用 敏感/耐药配对GBM细胞，并将这些变化与靶点抑制和药物敏感性相关联，3） 确定药物诱导的13 C丙酮酸至130乳酸转化的变化是否平行靶向 体外抑制和药物敏感性在体内异种移植物中也是如此，和4）确定治疗诱导的 通过超极化130 MRSI检测的丙酮酸代谢的改变可以单独使用，或与 与其他成像标志物组合，作为临床中靶点抑制和早期反应的生物标志物 复发性GBM患者的试验。与项目1密切互动，所有共享资源核心将 这对成功进行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.