Molecular Imaging Markers for Glutaminolysis in Breast Cancer

乳腺癌谷氨酰胺分解的分子成像标志物

• 批准号: 9215316
• 负责人: DAVID A. MANKOFF
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215316
• 关键词: Amino Acids; Anabolism; Animal Model; Biochemical; Biological Assay; Blood; Breast Cancer Model; Breast Cancer Treatment; Cell Line; Cells; Clinic; Clinical; Clinical Trials; Data; Dependence; Development; Drug Targeting; Energy Supply; Enzymes; Exhibits; Glioblastoma; Glucose; Glutamates; Glutaminase; Glutamine; Human; Image; Image Analysis; Individual; Label; Lymphoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Motivation; Nutrient; Oncogenes; Outcome; Pathway interactions; Patients; Pharmacodynamics; Phase; Play; Positron-Emission Tomography; Pre-Clinical Model; Production; Radioisotopes; Reporting; Research Design; Role; Testing; Therapeutic; Tumor Markers; Xenograft Model; Xenograft procedure; base; cancer subtypes; cancer therapy; clinical translation; design; driving force; effective therapy; glutamine analog; imaging biomarker; imaging modality; imaging probe; in vivo; inhibitor/antagonist; malignant breast neoplasm; molecular imaging; molecular subtypes; novel; pharmacodynamic biomarker; predictive marker; response; targeted treatment; tool; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor metabolism

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.

肿瘤特异性的代谢改变已越来越被认为是驾驶 肿瘤生长的力。谷氨酰胺（GLN）是血液中最丰富的氨基酸。葡萄糖 GLN是癌症使用的两种主要营养素来满足能源生产的需求 和生物合成。 GLN通过谷氨酰胺溶解途径代谢，该途径高度活跃 在许多侵略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。第一个且限制的步骤 谷氨酰胺溶解由线粒体谷氨酰胺酶（GLS）催化，将谷氨酰胺转化为 谷氨酸。靶向谷氨酰胺溶解途径关键步骤的药物正在开发，并且 有希望的GL抑制剂已升级为早期临床试验。但是，没有 当前临床上可行的方法估计癌症谷氨酰胺代谢水平，也不是 有非侵入性标记物可以报告GLS抑制剂的药效学（PD）作用。 这些未满足的需求为开发基于成像的方法来衡量的动力提供了强大的动力 细胞谷氨酰胺分解以指导靶向GLS的疗法，这是该建议的重点。 为了在癌症中询问体内谷氨酰胺代谢，我们的中心已经设计和 开发了两个正电子发射断层扫描（PET）成像探针：l- [5-11c]谷氨酰胺 （[11C] GLN）和（2S，4R）-4 [18F]谷氨酰胺（[[18F]氟谷氨酰胺或[18F] 4F GLN）。这个项目的目标 使用[11C] GLN和[18F] 4F GLN PET开发和验证定量分析工具 人类乳腺癌异种移植物。根据我们的初步研究，我们设计了研究 为了测试中心假设，即[18F] 4F-GLN的分布体积是肿瘤的标志 谷氨酰胺池是谷氨酰胺代谢的间接度量，而通量通过GL 通过[11C] GLN PET测量是肿瘤GLS活性的真实标记。这些实用性 报告新型谷氨酰胺酶抑制剂的药效学作用的标记将开发 并使用基于不同乳房细胞系的乳腺癌异种移植模型进行了验证 对谷氨酰胺的依赖程度不同的癌症亚型。 拟议项目的结果将满足未满足的定量临床需求， 能够预测和测量对谷氨酰胺靶向的反应的非侵入性工具 疗法。这些项目完成该项目后，这些工具将准备好进行临床试验 这种疗法在患者的发展和部署中的关键作用。