PET Kinetic Modeling of Inhibiting Glycolysis in Ovarian Cancer

抑制卵巢癌糖酵解的 PET 动力学模型

基本信息

批准号：
9109588
负责人：
Norbert E. Avril
金额：
$ 22.23万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-13 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109588
关键词：
6-Phosphofructo-2-kinase Abdominal Cavity Accounting Animal Model Animals Binding Blood Blood specimen C14 isotope Cancer cell line Carrier Proteins Cell Line Cell membrane Cells Cisplatin Combined Modality Therapy Cytotoxic agent Data Deoxyglucose Development Disease Dose Energy Metabolism Enzymes Epithelial ovarian cancer Evaluation Event Future Glucose Glucose Transporter Glucose-6-Phosphate Glycolysis Goals Gynecologic Health Hexokinase 2 Hour Image In Vitro Kinetics Lonidamine Maintenance Malignant Neoplasms Malignant neoplasm of ovary Measures Metabolic Metabolic Pathway Methods Modeling Oxidative Phosphorylation Oxygen Consumption Pathway interactions Patients Phosphorylation Physiological Platinum Positron-Emission Tomography Production Rattus Relapse Research Research Project Grants SLC2A1 gene Skeletal Muscle Staging Time Tissues Tracer Translating Tumor Tissue Up-Regulation Validation X-Ray Computed Tomography base cancer cell chemotherapy data acquisition extracellular glucose analog glucose metabolism glucose transport glucose uptake imaging agent in vivo in vivo Model indexing inhibitor/antagonist interstitial microPET/CT non-invasive imaging novel response taxane treatment response treatment strategy tumor tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Our research is focused on targeting the glucose metabolism of ovarian cancer. We are developing imaging based treatment strategies to guide and optimize the inhibition of metabolic pathways. As proof of concept, we will inhibit three targets within the glycolytic pathway: a) the glucose transport into cells by inhibiting glucose transporter (Glut) proteins b) the phosphorylation of glucose to glucose-6-phosphate by inhibiting hexokinase-2 (HK-2), and c) the inhibition of phosphofructokinase-2 (PFK-2). CG-5 binds and inhibits the activity of transmembrane glucose transporter; Lonidamine targets mitochondrially-bound HK-2; and 3PO inhibits PFK-2. Positron emission tomography (PET) using [F-18]Fluorodoxyglucose ([F-18]-2-FDG) allows for noninvasive imaging of tumor glucose uptake. In addition, we will use a novel agent [F-18]-6-FDG, which is established in our labs and, as a non-phosphorylated glucose analog, provides mechanistic data specifically about the transport of glucose through the cell membrane. A significant challenge is to define and quantify metabolic responses to glycolytic pathway inhibition, for which we will develop and validate appropriate PET kinetic models in vivo. Therefore we will: a) Target ovarian cancer by specific inhibition of the glycolytic pathway in vitro; b) Perform [F-18]FDG microPET/CT imaging in ovarian cancer bearing animals during the inhibition of the glycolytic pathway; and c) Develop and validate kinetic models for analysis of [F-18]FDG in vivo. With the successful completion of these aims we will have developed PET analysis approaches for different mechanisms inhibiting the glycolytic pathway, which is important to guide and optimize their future use.

描述（由适用提供）：我们的研究重点是针对卵巢癌的葡萄糖代谢。我们正在制定基于成像的治疗策略，以指导和优化代谢途径的抑制。作为概念证明，我们将抑制糖酵解途径内的三个靶标：a）葡萄糖通过抑制葡萄糖转运蛋白（GLUT）蛋白b）葡萄糖通过抑制己糖酶-2（HK-2）（HK-2）的葡萄糖-6-磷酸盐的磷酸化而转运到细胞中。 CG-5结合并抑制转运葡萄糖转运蛋白的活性；隆田胺靶向线粒体结合的HK-2； 3PO抑制PFK-2。正电子发射断层扫描（PET）使用[F-18]氟氧基葡萄糖（[F-18] -2-FDG）允许对肿瘤葡萄糖摄取的无创成像。此外，我们将使用一种新型药物[F-18] -6-FDG，是a）通过特异性抑制体外糖酵解途径的靶向卵巢癌； b）在抑制糖酵解途径期间，在卵巢癌轴承动物中执行[F-18] FDG MicroPET/CT成像； c）开发和验证动力学模型，以分析体内[F-18] FDG。随着这些目标的成功完成，我们将开发出抑制糖酵解途径的不同机制的宠物分析方法，这对于指导和优化其未来使用非常重要。