Glycine metabolism in cancer

项目摘要 癌细胞有一种独特的新陈代谢来支持它们的病理 扩散。以这种新陈代谢为靶点导致了许多现有的化疗方法 在今天的临床上，如抗叶酸。氨基酸甘氨酸主要是由 叶酸代谢，一种在癌症中几乎普遍上调的途径。甘氨酸 支持重要的生物合成过程，包括蛋白质、嘌呤和谷胱甘肽 综合。此外，甘氨酸的分解代谢过程最近被证明是 在癌症干细胞和胶质母细胞瘤中很重要。在最新公布的数据中，我 证明甘氨酸支持的抗氧化剂的产生对癌细胞至关重要 成长。这项提议试图定量描述癌症中的甘氨酸代谢。 并验证了叶酸介导的甘氨酸合成支持谷胱甘肽的假设 生产，从而氧化还原动态平衡。在这些努力中，我将受益于一个新的小 我发现的分子，它能有效地抑制甘氨酸合成的两种同工酶 酶SHMT。在目标1中，我将使用同位素示踪剂来量化甘氨酸的生产和 在正常细胞和癌细胞中的消耗通量，并将这些发现应用于体内。在AIM 2、我将进一步开发SHMT抑制剂，并在B细胞小鼠模型上进行测试 淋巴瘤是一种甘氨酸输入缺陷的肿瘤类型，因此 体外敏感的SHMT抑制作用。总的来说，这些实验将奠定基础 针对甘氨酸代谢作为一种新的癌症治疗方法。在.之下 在K99期间，我的主要导师和我的合作者团队的指导，这 建议书将使我成功地从目前的指导职位过渡到 独立研究小组组长。

Project Summary Cancer cells have a distinct metabolism that supports their pathological proliferation. Targeting this metabolism has led to many of the existing chemotherapies in the clinic today such as antifolates. The amino acid glycine is primarily produced by folate metabolism, a pathway that is nearly universally upregulated in cancer. Glycine supports important biosynthetic processes including protein, purine and glutathione synthesis. In addition, glycine catabolic processes have recently been shown to be important in cancer stem cells and glioblastoma. In newly published data, I demonstrated that glycine-supported antioxidant production is crucial for cancer cell growth. This proposal seeks to quantitatively characterize glycine metabolism in cancer and to test the hypothesis that folate-mediated glycine synthesis supports glutathione production and thus redox homeostasis. In these efforts, I will benefit from a new small molecule that I discovered, which potently inhibits both isozymes of the glycine synthetic enzyme SHMT. In Aim 1, I will use isotope tracers to quantitate glycine production and consumption fluxes in normal and cancer cells, and apply these findings in vivo. In Aim 2, I will further develop the SHMT inhibitor and test it in a mouse model of B-cell lymphoma, a tumor type that is defective in glycine import and accordingly highly sensitive SHMT inhibition in vitro. Collectively, these experiments will lay the groundwork for targeting of glycine metabolism as a new therapeutic approach in cancer. Under the guidance of my primary mentor and my team of collaborators during the K99 period, this proposal will allow me to successfully transition from my current mentored position into a independent research group leader.