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

项目概要/摘要 这项工作探讨了通过饮食控制与靶向治疗相结合来治疗胰腺癌的可能性。 甘氨酸-丝氨酸-一碳（1C）代谢的抑制剂。1C代谢在核苷酸合成中起重要作用 合成、氧化还原稳态和表观遗传学。甘氨酸和丝氨酸可以来自饮食或内源性 合成，其中酶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消耗减缓肿瘤 增长在这里，这项工作将剖析甘氨酸与丝氨酸对肿瘤生长的相对重要性，采用 了解饮食控制对肿瘤影响的最先进分析方法 代谢，并测试假设，结合饮食操纵与靶向途径抑制剂， 增强胰腺导管腺癌小鼠肿瘤模型的功效。为此，Aim 1将 单独研究饮食或药物干预：无甘氨酸饮食、无丝氨酸饮食或SHMT抑制剂。 将使用液相色谱-质谱法（LC-MS）测量循环和肿瘤代谢物 程度.将13 C-葡萄糖、13 C-丝氨酸和13 C-甘氨酸输注到小鼠中将评估全身性和肿瘤特异性 甘氨酸、丝氨酸和1C单位的产生和命运。目标2将膳食和药理学结合起来 干预措施，旨在更充分地耗尽甘氨酸，丝氨酸或1C单位。具体来说，无甘氨酸饮食将是 与SHMT抑制剂配对以最大限度地消耗甘氨酸。不含丝氨酸的饮食将与抑制去乙酰化酶的作用相结合。 新丝氨酸合成途径（PHGDH抑制剂）以最大限度地消耗丝氨酸。无丝氨酸饮食将配对 与SHMT抑制剂一起使用，以最大限度地损害丝氨酸驱动的1C单位生产。在每种情况下， 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 追踪）将受到监测。这将检验假设，即1C单位的更大消耗，无论是从 单独或双重饮食-药物操作，增加抗肿瘤活性。这也将提供一个基础 合理设计优化的治疗方案的知识，可以转化为临床。更 一般来说，本研究旨在建立深入的代谢研究的饮食药物的效用， 联合用药以推动新治疗方案的合理设计。该计划旨在提供培训 在先进技术和新的治疗方法的发展，定位申请人为一个 在癌症表观遗传学，饮食和新陈代谢的界面上的高影响力职业。

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.