Glycine metabolism in cancer

项目摘要 癌细胞具有独特的代谢，支持其病理学特征。 增殖靶向这种代谢导致了许多现有的化学疗法 比如抗叶酸剂氨基酸甘氨酸主要由以下方法产生： 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 合成.此外，甘氨酸分解代谢过程最近已被证明是 在癌症干细胞和胶质母细胞瘤中很重要。在新公布的数据中，我 表明甘氨酸支持的抗氧化剂生产对癌细胞至关重要， 增长该提案旨在定量表征癌症中的甘氨酸代谢 并验证叶酸介导的甘氨酸合成支持谷胱甘肽的假设 生产和因此氧化还原稳态。在这些努力中，我将受益于一个新的小 我发现的一种分子，它可以有效地抑制甘氨酸合成酶的两种同工酶， 酶SHMT。在目标1中，我将使用同位素示踪剂来定量甘氨酸的产生， 消耗通量在正常和癌细胞，并在体内应用这些发现。在Aim中 2、我将进一步开发SHMT抑制剂，并在小鼠B细胞模型中进行测试。 淋巴瘤是一种甘氨酸输入缺陷的肿瘤类型，因此高度依赖于甘氨酸。 体外敏感的SHMT抑制作用。总的来说，这些实验将为 用于靶向甘氨酸代谢作为癌症的新治疗方法。下 在K99期间，我的主要导师和我的合作者团队的指导下， 建议将使我能够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.