Lactate Transport as a Therapeutic Target in Glioma

乳酸转运作为神经胶质瘤的治疗靶点

基本信息

批准号：
7626878
负责人：
Saroj Priyantha Mathupala
金额：
$ 23.46万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7626878
关键词：
12 year old Adverse effects Aerobic Affect Affinity American Animals Apoptosis Behavior Biochemical Biological Assay Blood - brain barrier anatomy Blood Glucose Brain Brain Neoplasms Caspase-1 Cell Death Cell Line Cell Surface Receptors Cells Cellular Assay Cessation of life Characteristics Child Clinical Commit Computer Simulation Consumption DNase-I Footprinting Data Dextrans Diagnosis Diffuse Down-Regulation Doxycycline Effectiveness Elderly Elements Encapsulated Engineering Environment Enzymes Erythropoiesis Estrogens Event Excretory function Exons Extracellular Matrix Flow Cytometry Fluorescence Fluorescence Spectrometry Follow-Up Studies Future GATA1 protein Gel Gelatinase A Gelatinase B Generations Genes Glioblastoma Glioma Glucose Glycolysis Goals Growth Hormonal Hydrogen Peroxide Hypoxia Immunoblotting Implant In Vitro Interstitial Collagenase Introns Invaded Knowledge Laboratories Lactate Transporter Lactic acid Lead Left Libraries Luciferases Magnetic Resonance Imaging Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Metabolic Metabolism Methods Minocycline Mitochondria Modeling Molecular Molecular Profiling Monitor Necrosis Neoplasm Metastasis Normal tissue morphology Nuclear Extract Nude Rats Operative Surgical Procedures Oxygen Pathway interactions Peptide Hydrolases Peroxides Pharmaceutical Preparations Phorbol Esters Positron-Emission Tomography Process Proliferating Protein Isoforms Proteins Publications Radiation therapy Radiosurgery Reaction Reader Regulation Reporter Genes Research Resort Retroviridae Role Screening procedure Sensitivity and Specificity Serum Signal Pathway Signal Transduction Signal Transduction Pathway Slice Small Interfering RNA Small Molecule Chemical Library Societies Staging Stimulus Stromal Neoplasm System TNFRSF6 gene Techniques Testing Tetanus Helper Peptide Therapeutic Therapeutic Intervention Tissue Extracts Tissues Trans-Activators Transcriptional Regulation Tumor Bank Tumor Tissue Tumor-Derived United States Up-Regulation Urokinase Xenograft procedure analog base brain cell brain tissue chemotherapy cinnamic acid cis acting element cranium design dextran drinking water enhanced green fluorescent protein fluorophore gel mobility shift assay glioma cell line glucose metabolism human GATA1 protein in vitro Assay in vivo inhibitor/antagonist lactate 2-monooxygenase matrigel mortality mutant neoplastic cell new therapeutic target novel novel strategies outcome forecast pressure promoter research study small molecule therapeutic development therapeutic target tool tumor tumor registry

项目摘要

DESCRIPTION (provided by applicant): An abnormally high rate of glycolysis, i.e., rapid consumption of glucose and metabolism to lactic acid, is a hallmark of all malignant tumors. Our long-term goal is to elucidate the molecular basis for this aberrant behavior, and harness that knowledge towards development of therapeutic strategies against glioblastoma multiforme (GBM), the most malignant and lethal of brain tumors. We hypothesize that inhibition of lactate efflux by these tumors will debilitate their metabolism and cause their death, based on our observations that 1] lactic acid is effluxed to the tumor microenvironment in large quantities by GBMs, 2] specific lactate transporter isoforms are highly expressed in GBMs in contrast to normal brain tissue, 3] inhibition of lactate transporter expression or their function in GBM derived cell lines, both in vitro and in vivo, halted their ability to efflux lactic acid, and resulted in their rapid destruction. The specific aims are to: 1. Identify the key signaling pathways that regulate lactate transporter expression in GBMs. Promoter of MCT2, the lactate transporter predominantly expressed in GBMs, will be used as the model to distinguish the primary metabolites and trans-activating factors that are involved. 2. Investigate how lactate efflux affects the invasive potential of GBMs. Lactic acid was recently identified to influence the remodeling of extracellular matrix by tumors. We will query the glioma micro-environment via organotypic brain-slice cultures for induction of key stromal and tumor-derived proteases by lactic acid, and correlate the effects on the invasive process. 3. Examine how signaling pathways common to erythropoiesis interact with the MCT2 promoter. Cis-acting elements common in erythropoietic genes are the most prolific on the proximal MCT2 promoter. We will investigate how these motifs and their trans-acting factors regulate MCT2 expression in GBMs, and the rationale for their presence. 4. Develop an in vitro cellular assay for rapid screening of small molecule drugs to identify novel lactate transporter inhibitors. Derivatives of cinnamic acid are the only known competitive inhibitors of lactate transporters. We will utilize gel micro-encapsulated-cell based techniques to design an in vitro assay for screening of small molecule chemical libraries to identify new drugs to target lactate transport. Every year more than 17,000 people in the US, mostly children 3 to 12 years old, and adults 40 to 70 years old, find out they have malignant brain cancer. Tragically, 90% of them still die within 6 to 12 months, even after surgery, radiation treatment, and chemotherapy. Thus, we need new ways to target this deadly cancer. We plan to test a novel method to "pickle-the-tumor-to-death," while leaving healthy brain cells intact.

描述（由申请人提供）：糖酵解的异常高速率，即葡萄糖和代谢迅速消耗乳酸，是所有恶性肿瘤的标志。我们的长期目标是阐明这种异常行为的分子基础，并利用对针对胶质母细胞瘤多形（GBM）的治疗策略发展的知识，这是脑肿瘤的最恶性和致命性。我们假设这些肿瘤抑制乳酸外排会使它们的新陈代谢衰弱并导致其死亡，这是基于我们的观察结果，即1]乳酸被GBMS大量以大量的GBMS，2]特异性乳酸转运蛋白同工型在大量的肿瘤微环境中。与正常的脑组织相比，GBMS，3]抑制乳酸转运蛋白的表达或它们在体外和体内的GBM衍生细胞系中的功能，使它们停止了排出乳酸的排出能力，并导致了快速破坏。具体目的是：1。确定调节GBM中乳酸转运蛋白表达的关键信号通路。 MCT2的启动子，主要在GBM中表达的乳酸转运蛋白，将用作区分涉及的主要代谢产物和反式激活因子的模型。 2。研究乳酸外排如何影响GBM的侵入性潜力。最近发现乳酸会影响肿瘤对细胞外基质的重塑。我们将通过器官型脑片培养物查询胶质瘤微环境，以通过乳酸诱导关键的基质和肿瘤衍生的蛋白酶，并将对侵入性过程的影响相关。 3。检查促红细胞生成的信号传导途径如何与MCT2启动子相互作用。红细胞生成基因中常见的顺式作用元素是近端MCT2启动子中最多产的。我们将研究这些基序及其跨作用因子如何调节GBM中的MCT2表达，以及它们存在的基本原理。 4。开发一种体外细胞测定法，以快速筛选小分子药物，以鉴定新型的乳酸转运蛋白抑制剂。肉桂酸的衍生物是乳酸转运蛋白唯一已知的竞争抑制剂。我们将利用凝胶微封装的基于基于细胞的技术来设计一种体外测定，用于筛选小分子化学文库，以鉴定新药物以靶向乳酸转运。在美国，每年有17,000多人，主要是3至12岁的儿童，成年人40至70岁，发现他们患有恶性脑癌。可悲的是，即使在手术，放射治疗和化学疗法后，其中90％的人仍然在6到12个月内死亡。因此，我们需要新的方法来靶向这种致命的癌症。我们计划测试一种新方法，以“泡菜对死亡”，同时使健康的脑细胞完好无损。