Hyperpolarized NMR for Studies of Cancer Therapies Targeting the Warburg Effect

超极化核磁共振用于针对 Warburg 效应的癌症治疗研究

基本信息

批准号：
8502084
负责人：
Aaron Keith Grant
金额：
$ 36.11万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-19 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8502084
关键词：
Accounting Acute Affect Bicarbonates Cancer Etiology Cancer Patient Cancer cell line Cause of Death Cell Line Cell Respiration Cells Cessation of life Characteristics Cisplatin Citric Acid Cycle Clinical Combined Modality Therapy Development Dichloroacetate Disease Dose Drug Combinations Drug Targeting Effectiveness Emerging Technologies Environment Enzymes Epidermal Growth Factor Receptor Exhibits Glucose Heart Diseases Hypoxia In Vitro Intervention Lactate Dehydrogenase Lactic acid Long-Term Effects Lung Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Measurement Measures Metabolic Metabolic Pathway Metabolism Methods Molecular Target Monitor Mutation Neoplasm Metastasis Normal tissue morphology Oxygen Patients Pharmaceutical Preparations Phenotype Platinum Positron-Emission Tomography Production Pyruvate Reliance Signal Transduction Spectrum Analysis Staining method Stains Techniques Testing Time Tissues Translations Vascular Endothelial Growth Factors Warburg Effect Work Xenograft Model cancer cell cancer prevention cancer therapy cancer type clinical practice design fluorodeoxyglucose positron emission tomography glucose uptake improved in vitro Assay inhibitor/antagonist interest lactate dehydrogenase A neoplastic cell new technology patient population public health relevance pyruvate dehydrogenase response tool treatment response tumor tumor growth tumor metabolism tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): There is a pressing need for improved therapies for many types of cancer. Here we propose to investigate cancer metabolism as a target for therapy. Many types of cancer exhibit the Warburg effect, taking up large quantities of glucose and metabolizing it into lactate rather than oxidizing it in the Krebs cycle. The Warburg effect may confer a survival advantage on cancer cells. By inhibiting specific enzymes that are involved in lactate production, it may be possible to reverse the Warburg effect and thereby selectively harm cancer cells. We will study several drugs that accomplish this by inhibiting lactate dehydrogenase or by up-regulating the activity of pyruvate dehydrogenase. A second major focus of the work is the use of hyperpolarized 13C NMR of pyruvate and its metabolites to non-invasively monitor tumor metabolism. Hyperpolarized NMR will be employed to assess the effects of different interventions, and to design a combination of drugs that brings about a maximal reversal of the Warburg effect. We will investigate the utility of hyperpolarized NMR as a technique for assessing the 'on-target' effects of various metabolic interventions, and determine whether shifts in metabolism measured with hyperpolarization can provide an early predictor of tumor response to therapy. In addition, we will investigate the use of metabolic therapies in conjunction with cisplatin, and compare the utility of hyperpolarized NMR and FDG PET in assessing tumor response.

描述（由申请人提供）：迫切需要改进多种癌症的治疗方法。在这里，我们建议研究癌症代谢作为治疗目标。许多类型的癌症都表现出瓦伯格效应，吸收大量葡萄糖并将其代谢为乳酸，而不是在克雷布斯循环中将其氧化。瓦尔堡效应可能赋予癌细胞生存优势。通过抑制参与乳酸生成的特定酶，有可能逆转瓦尔堡效应，从而选择性地伤害癌细胞。我们将研究几种通过抑制乳酸脱氢酶或上调丙酮酸脱氢酶活性来实现这一目标的药物。该工作的第二个主要重点是使用丙酮酸及其代谢物的超极化 13C NMR 来非侵入性监测肿瘤代谢。超极化核磁共振将用于评估不同干预措施的效果，并设计药物组合以最大程度地逆转瓦尔堡效应。我们将研究超极化核磁共振作为评估各种代谢干预的“目标”效果的技术的实用性，并确定用超极化测量的代谢变化是否可以提供肿瘤对治疗反应的早期预测。此外，我们将研究代谢疗法与顺铂联合使用，并比较超极化 NMR 和 FDG PET 在评估肿瘤反应中的效用。