Metabolic Constraints on Cancer Cell Proliferation

项目概要/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。我们最近观察到，维持天冬氨酸水平是 通过支持癌细胞增殖所需的核苷酸和蛋白质的合成， 增殖重要的是，初步数据表明，细胞内天冬氨酸是一种内源性代谢产物， 限制肿瘤生长。天冬氨酸对细胞是相对不可渗透的，必须从其它氨基酸合成。 代谢前体因此，抑制癌细胞用于维持天冬氨酸水平的机制是一种有效的方法。 治疗癌症的潜在方法。该提案使用几种方法来靶向天冬氨酸水平， 确定天冬氨酸在其中最受限制的癌症。具体来说，我们将测试假设， 天冬氨酸是某些肿瘤内源性代谢限制（目的1），还原性谷氨酰胺代谢 支持缺氧细胞中天冬氨酸的产生（Aim 2），改变天冬酰胺的合成可以影响 天冬氨酸水平和癌细胞增殖（Aim 3）。我们将用细胞培养来测试 并使用癌症的临床前小鼠模型来确定它们在体内的功效。在一起， 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。这 职业发展奖也将是我作为一个科学家的发展至关重要，为我提供指导， 在马萨诸塞州著名的科赫综合癌症研究所的培训期间， 技术.这段时间将用于发展我的科学思想，提高我的工作能力， 最忠实地再现人类疾病的癌症小鼠模型。科学的进步 从这个建议和培训期间将是至关重要的，我的最终目标是建立一个独立的 研究癌细胞增殖的代谢限制的研究小组。

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 recently observed that maintaining aspartate levels is critical for cancer cell proliferation by supporting the synthesis of the nucleotides and protein needed for proliferation. Importantly, preliminary data has 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 test the hypotheses that aspartate is an endogenous metabolic limitation for some tumors (Aim 1), that reductive glutamine metabolism supports aspartate production in hypoxic cells (Aim 2), and that 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 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. This career development award will also be critical to my development as a scientist by providing me with mentored training period at the renowned Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology. This time will be used to develop my scientific ideas and increase my competency in working with the mouse models of cancer that most faithfully recapitulate human disease. The scientific advances learned from this proposal and the training period will be critical to my ultimate goal of establishing an independent research group studying the metabolic constraints of cancer cell proliferation.