Metabolic Constraints on Cancer Cell Proliferation

项目总结/摘要 与产生癌症的正常组织相比，癌症显示出改变的细胞代谢。一 有希望的治疗方法是利用这些差异，设计干预措施， 癌细胞的代谢需求。我们已经观察到，维持天冬氨酸水平对于 通过支持增殖所需的核苷酸和蛋白质的合成来抑制癌细胞增殖。我们 在肿瘤模型中的研究也表明，细胞内天冬氨酸是一种内源性代谢限制， 肿瘤生长天冬氨酸对细胞是相对不可渗透的，必须从其他代谢产物合成。 前体因此，抑制癌细胞用于维持天冬氨酸水平的机制是一种潜在的方法 治疗癌症该提案使用了几种方法来靶向天冬氨酸水平并确定癌症 其中天冬氨酸是最有限的。具体地说，我们将确定天冬氨酸是一种 内源性代谢限制肿瘤（目的1），研究还原性谷氨酰胺代谢是否支持 缺氧细胞中天冬氨酸的产生（目的2），并测试是否改变天冬酰胺合成可以影响天冬氨酸 水平和癌细胞增殖（目标3）。我们将使用细胞培养来测试这些机制的要素， 假设，并使用癌症的临床前小鼠模型来确定它们在体内的功效。所有这些 研究将探索新的治疗方法，以靶向癌细胞的代谢，并确定 最适合部署的情况。因此，该项目的长期科学目标是改善 通过识别新的治疗靶点并在小鼠癌症模型中验证它们来治疗癌症。

Project Summary/Abstract Cancers display altered cellular metabolism compared to the normal tissues from which they arise. One promising therapeutic approach is to take advantage of these differences by designing interventions that target the metabolic requirements of cancer cells. We have observed that maintaining aspartate levels is critical for cancer cell proliferation by supporting the synthesis of the nucleotides and protein needed for proliferation. Our work in tumor models has also indicated that intracellular aspartate is an endogenous metabolic limitation of tumor growth. Aspartate is relatively impermeable to cells and must be synthesized from other metabolic precursors. Thus, inhibiting the mechanisms cancer cells use to maintain aspartate levels is a potential method of treating cancer. This proposal uses several approaches to target aspartate levels and determine the cancers in which aspartate is most limiting. Specifically, we will determine the conditions in which aspartate is an endogenous metabolic limitation for tumors (Aim 1), investigate if reductive glutamine metabolism supports aspartate production in hypoxic cells (Aim 2), and test if altering asparagine synthesis can affect aspartate levels and cancer cell proliferation (Aim 3). We will use cell culture to test the mechanistic elements of these hypotheses and use preclinical mouse models of cancer to determine their efficacy in vivo. Together, these studies will investigate new therapeutic methods to target the metabolism of cancer cells and to identify the situations in which they are best deployed. The long-term scientific goal of this project is therefore to improve cancer therapy by identifying new therapeutic targets and validating them in mouse models of cancer.