Hyperpolarized NMR for Studies of Cancer Therapies Targeting the Warburg Effect

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，我们建议研究癌症新陈代谢作为治疗的靶点。许多类型的癌症表现出沃堡效应，在克雷布斯循环中摄取大量葡萄糖并将其代谢成乳酸，而不是将其氧化。沃堡效应可能会给癌细胞带来生存优势。通过抑制参与乳酸产生的特定酶，有可能逆转沃伯格效应，从而选择性地损害癌细胞。我们将研究几种药物，通过抑制乳酸脱氢酶或上调丙酮酸脱氢酶的活性来实现这一点。这项工作的第二个主要焦点是使用丙酮酸及其代谢物的超极化13CNMR来非侵入性地监测肿瘤代谢。超极化核磁共振将被用来评估不同干预措施的效果，并设计一种能够最大限度地逆转华宝效应的药物组合。我们将研究超极化核磁共振作为一种评估各种代谢干预的“靶向”效应的技术的实用性，并确定超极化测量的代谢变化是否可以提供肿瘤治疗反应的早期预测指标。此外，我们还将研究代谢疗法与顺铂联合使用的情况，并比较超极化核磁共振和FDG PET在评估肿瘤反应中的作用。

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.