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：
7417938
负责人：
Saroj Priyantha Mathupala
金额：
$ 23.45万
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/7417938
关键词：
12 year old Adverse effects Aerobic Affect Affinity American Brain Tumor Association American Type Culture Collection Animals Apoptosis Appendix 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 Condition Consumption DNase-I Footprinting Data Development Dextrans Diagnosis Diffuse Down-Regulation Doxycycline Effectiveness Elderly Elements Encapsulated Endopeptidases 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 Invasive 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 Principal Investigator Process Proliferating Protein Isoforms Proteins Publications Radiation therapy Radiosurgery Rate Reaction Reader Registries Regulation Reporter Genes Research Research Personnel 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 Tetradecanoylphorbol Acetate Therapeutic Therapeutic Intervention Tissue Extracts Tissues Trans-Activators Transcriptional Activation 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 glucose metabolism human GATA1 protein in vitro Assay in vivo inhibitor/antagonist lactate 2-monooxygenase matrigel mortality mutant neoplastic cell novel novel strategies novel therapeutics outcome forecast pressure programs promoter research study small molecule therapeutic target tool tumor

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）：异常高的糖酵解率，即葡萄糖的快速消耗和代谢为乳酸，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，并利用这些知识来开发针对多形性胶质母细胞瘤（GBM）（最恶性和最致命的脑肿瘤）的治疗策略。基于我们的观察，我们假设这些肿瘤对乳酸流出的抑制会削弱其代谢并导致其死亡，即 1] 乳酸通过 GBM 大量流出到肿瘤微环境，2] 特定的乳酸转运蛋白亚型在肿瘤微环境中高度表达。 GBM 与正常脑组织相反，3] 在体外和体内抑制 GBM 衍生细胞系中的乳酸转运蛋白表达或其功能，会阻止其流出能力乳酸，并导致其快速破坏。具体目标是： 1. 确定调节 GBM 中乳酸转运蛋白表达的关键信号通路。 MCT2 的启动子是主要在 GBM 中表达的乳酸转运蛋白，将用作区分所涉及的主要代谢物和反式激活因子的模型。 2. 研究乳酸外流如何影响 GBM 的侵袭潜力。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切片培养物查询神经胶质瘤的微环境，以通过乳酸诱导关键基质和肿瘤来源的蛋白酶，并将其对侵袭过程的影响关联起来。 3. 检查红细胞生成常见的信号通路如何与 MCT2 启动子相互作用。促红细胞生成基因中常见的顺式作用元件在近端 MCT2 启动子上最多产。我们将研究这些基序及其反式作用因子如何调节 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，用于快速筛选小分子药物，以鉴定新型乳酸转运蛋白抑制剂。肉桂酸衍生物是唯一已知的乳酸转运蛋白竞争性抑制剂。我们将利用基于凝胶微囊化细胞的技术来设计一种体外测定法，用于筛选小分子化学库，以确定靶向乳酸转运的新药物。美国每年有超过 17,000 人发现患有恶性脑癌，其中大部分是 3 至 12 岁的儿童和 40 至 70 岁的成年人。可悲的是，即使在手术、放射治疗和化疗之后，90% 的患者仍然在 6 至 12 个月内死亡。因此，我们需要新的方法来针对这种致命的癌症。我们计划测试一种“腌制肿瘤至死”的新方法，同时保持健康的脑细胞完好无损。