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

• 批准号: 8653939
• 负责人: Aaron Keith Grant
• 金额: $ 35.02万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 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/8653939
• 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

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）：迫切需要改善许多类型的癌症的疗法。 在这里，我们建议研究癌症代谢作为治疗的靶标。 许多类型的癌症表现出沃堡效应，吸收大量葡萄糖并将其代谢成乳酸，而不是在克雷布斯周期中氧化。 Warburg效应可能会赋予癌细胞的生存优势。 通过抑制参与乳酸产生的特定酶，有可能扭转沃堡效应，从而选择性地损害癌细胞。我们将通过抑制乳酸脱氢酶或上调丙酮酸脱氢酶的活性来研究几种来实现此目的的药物。这项工作的第二个主要重点是使用超极化的13C NMR丙酮酸及其代谢产物非侵入性监测肿瘤代谢。 将采用超极化NMR来评估不同干预措施的影响，并设计一种药物的组合，从而带来最大的Warburg效应逆转。 我们将研究超极化NMR作为评估各种代谢干预措施的“目标”效应的一种技术，并确定用超极化测量的代谢中的转移是否可以提供对治疗肿瘤反应的早期预测指标。此外，我们将研究代谢疗法与顺铂结合使用，并比较超极化NMR和FDG PET在评估肿瘤反应中的实用性。