Molecular Imaging Markers for Glutaminolysis in Breast Cancer

肿瘤特异性代谢改变越来越被认为是一种驱动因素， 肿瘤生长的力量。谷氨酰胺（Gln）是血液中最丰富的氨基酸。葡萄糖 和谷氨酰胺是两种主要的营养物质利用的癌症，以满足需求的能源生产 和生物合成。谷氨酰胺通过高活性的β-氨基分解途径代谢 在许多侵袭性形式的人类癌症中，包括三阴性乳腺癌（TNBC）， 胰腺癌和肺癌、淋巴瘤和胶质母细胞瘤。第一和速率限制步骤 谷氨酰胺分解由线粒体谷氨酰胺酶（GLS）催化，其将谷氨酰胺转化为谷氨酰胺。 谷氨酸盐。正在开发针对多巴胺分解途径关键步骤的药物， 有希望的GLS抑制剂已经进入早期临床试验阶段。但没有 目前临床上可行的方法来估计癌症谷氨酰胺代谢的水平，也是 存在可以报告GLS抑制剂的药效学（PD）效应的非侵入性标志物。 这些未满足的需求为开发基于成像的方法来测量 以细胞胞内氨溶解为导向的GLS靶向治疗，是本次建议的重点。 为了研究癌症中的体内谷氨酰胺代谢，我们中心设计并 开发了两种正电子发射断层扫描（PET）成像探针：L-[5- 11 C]谷氨酰胺 （[11 C]Gln）和（2S，4 R）-4-[18F]谷氨酰胺（[18F]氟谷氨酰胺或[18F]4F-Gln）。该项目旨在 开发和验证[11 C]Gln和[18 F]4F-Gln PET的定量分析工具， 人乳腺癌异种移植物。基于我们的初步研究，我们设计了研究 为了检验中心假设，即[18 F]4F-Gln的分布体积是肿瘤的标志物 谷氨酰胺库是谷氨酰胺代谢的间接量度，而通过GLS的通量 通过[11 C]Gln PET测量的GLS是肿瘤GLS活性的真实标志物。这些的效用 将开发报告新型转氨酶抑制剂药效学作用的标志物 并使用基于不同乳腺癌细胞系的乳腺癌异种移植模型进行验证。 对谷氨酰胺依赖程度不同的癌症亚型。 拟议项目的结果将满足定量、 能够预测和测量对谷氨酰胺靶向的 治疗这些工具将准备临床试验完成后，本项目发挥 在患者中开发和部署此类疗法中发挥关键作用。

Tumor-specific metabolic alterations have been increasingly recognized as a driving force of tumor growth. Glutamine (Gln) is the most abundant amino acid in the blood. Glucose and Gln are two major nutrients utilized by cancers to meet the demand for energy production and biosynthesis. Gln is metabolized through the glutaminolysis pathway, which is highly active in many aggressive forms of human cancers, including triple-negative breast cancer (TNBC), pancreatic and lung cancer, lymphoma and glioblastoma. The first and rate-limiting step of glutaminolysis is catalyzed by mitochondrial glutaminase (GLS) that converts glutamine to glutamate. Drugs targeting key steps of glutaminolysis pathway are being developed, and promising inhibitors of GLS have advanced to early phase clinical trials. However, there are no current clinically feasible methods to estimate the level of cancer glutamine metabolism, nor is there a non-invasive marker that can report the pharmacodynamic (PD) effect of GLS inhibitors. These unmet needs provide strong motivation to develop imaging-based methods to measure cellular glutaminolysis in order to direct GLS-targeted therapy, the focus of this proposal. To interrogate in vivo glutamine metabolism in cancer, our Center has designed and developed two positron emission tomography (PET) imaging probes: L-[5-11C]Glutamine ([11C]Gln) and (2S,4R)-4[18F]Glutamine ([18F]Fluoroglutamine or [18F]4F-Gln ). This project aims to develop and validate quantitative analysis tools for [11C]Gln and [18F]4F-Gln PET using human breast cancer xenografts. Based on our preliminary studies, we have designed studies to test the central hypothesis that the distribution volume of [18F]4F-Gln is a marker of tumor glutamine pool that is an indirect measure of glutamine metabolism, while flux through GLS measured by [11C]Gln PET is an authentic marker of tumor GLS activity. The utility of these markers to report the pharmacodynamic effect of novel glutaminase inhibitor will be developed and validated using breast cancer xenograft models based on cell lines of different breast cancer subtype with varied degrees of dependence on glutamine. The outcome of the proposed project will fulfill the unmet clinical needs for quantitative, non-invasive tools capable of predicting and measuring response to glutamine-targeted therapies. These tools will be ready for clinical trials upon completion of this project to play a critical role in development and deployment of such therapies in patients.