Modulating one-carbon metabolism with diet and targeted inhibitors to treat cancer

项目摘要/摘要 这项工作探索了通过结合饮食控制和靶向治疗胰腺癌的潜力。 甘氨酸-丝氨酸-一碳(1C)代谢的抑制剂。1C代谢在核苷酸中起着重要作用 合成、氧化还原动态平衡和表观遗传学。甘氨酸和丝氨酸可以来自饮食，也可以来自内源性 合成，丝氨酸羟甲基转移酶(SHMT)将丝氨酸转化为甘氨酸和1C 单位。SHMT在大多数肿瘤中强烈上调，饮食中甘氨酸和丝氨酸的缺乏会减缓肿瘤的发展 成长。在这里，这项工作将剖析甘氨酸和丝氨酸对肿瘤生长的相对重要性，使用 了解饮食操作对肿瘤影响的最新分析方法 新陈代谢，并测试将饮食控制与靶向途径抑制剂相结合将 对小鼠胰腺导管腺癌肿瘤模型的增强作用。为此，目标一号将 单独研究饮食或药物干预：不含甘氨酸的饮食、不含丝氨酸的饮食或SHMT抑制剂。 液-质联用(LC-MS)将用于检测循环和肿瘤代谢物 级别。13C-葡萄糖、13C-丝氨酸和13C-甘氨酸注入小鼠体内将评估全身和肿瘤的特异性 甘氨酸、丝氨酸和1C单元的生产和去向。目标2将把饮食和药理结合起来 干预措施，旨在更充分地消耗甘氨酸、丝氨酸或1C单位。具体来说，不含甘氨酸的饮食将是 与SHMT抑制剂配对，最大限度地消耗甘氨酸。无丝氨酸饮食将伴随着对De的抑制 新丝氨酸合成途径(PHGDH抑制剂)，以最大限度地消耗丝氨酸。无丝氨酸饮食将成为配对 使用SHMT抑制剂，最大限度地损害丝氨酸驱动的1C单元的生产。在每种情况下，安全性、抗肿瘤 疗效、全身和肿瘤代谢物水平以及甘氨酸、丝氨酸和1C单位的来源(通过体内同位素 跟踪)将受到监控。这将检验这样一种假设，即1C单位的更大消耗，无论是来自 单独或双重饮食-药物操纵，增加抗肿瘤活性。这也将提供一个基础的 合理设计可转化为临床的优化治疗方案的知识。更多 总体而言，本研究旨在建立深入研究饮食药物代谢的实用性。 推动合理设计新的治疗方案的组合。该计划旨在提供培训 在先进技术和新治疗方法的开发方面，为申请者定位 在癌症表观遗传学、饮食和新陈代谢方面具有高度影响力的职业生涯。

Project Summary/Abstract This work explores the potential for treating pancreatic cancer by combining dietary manipulation with targeted inhibitors of glycine-serine-one-carbon (1C) metabolism. 1C metabolism plays an important role in nucleotide synthesis, redox homeostasis, and epigenetics. Glycine and serine can come either from diet or endogenous synthesis, with the enzyme serine hydroxymethyltransferase (SHMT) converting serine into glycine and a 1C unit. SHMT is strongly upregulated in most tumors and depletion of dietary glycine and serine slows tumor growth. Here, this work will dissect the relative importance of glycine versus serine to tumor growth, employ state-of-the-art analytical methodologies to understand the impact of dietary manipulations on tumor metabolism, and test the hypothesis that combining dietary manipulations with targeted pathway inhibitors will augment efficacy in mouse tumor models of pancreatic ductal adenocarcinoma. To this end, Aim 1 will investigate dietary or pharmacological interventions alone: glycine-free diet, serine-free diet, or SHMT inhibitor. Liquid chromatography-mass spectrometry (LC-MS) will be used to measure circulating and tumor metabolite levels. 13C-glucose, 13C-serine, and 13C-glycine infusions into mice will evaluate systemic and tumor-specific production and fate of glycine, serine, and 1C units. Aim 2 will integrate dietary and pharmacological interventions, aiming to more fully deplete glycine, serine, or 1C units. Specifically, glycine-free diet will be paired with SHMT inhibitor to maximally deplete glycine. Serine-free diet will be paired with inhibition of the de novo serine synthesis pathway (PHGDH inhibitor) to maximally deplete serine. Serine-free diet will be paired with SHMT inhibitor to maximally impair serine-driven 1C unit production. In each case, the safety, antitumor efficacy, systemic and tumor metabolite levels, and sources of glycine, serine, and 1C units (via in vivo isotopic tracing) will be monitored. This will test the hypothesis that greater depletion of 1C units, whether from individual or dual diet-drug manipulation, increases anti-tumor activity. This will also provide a foundational knowledge for rational design of optimized therapeutic regimens that can be translated into the clinic. More generally, this research aims to establish the utility of in-depth metabolic investigation of diet-drug combinations to drive rational design of new therapeutic regimens. The program is designed to provide training in both advanced technologies and development of new therapeutic approaches, positioning the applicant for a high-impact career at the interface of cancer epigenetics, diet, and metabolism.