Metabolic Constraints on Cancer Cell Proliferation

项目摘要/摘要 与产生癌症的正常组织相比，癌症表现出细胞代谢的改变。一 有希望的治疗方法是通过设计针对性的干预措施来利用这些差异 癌细胞的代谢需求。我们最近观察到，维持天冬氨酸水平是 通过支持合成所需的核苷酸和蛋白质对癌细胞的增殖至关重要 扩散。重要的是，初步数据表明，细胞内的天冬氨酸是一种内源性代谢。 限制肿瘤生长。天冬氨酸对细胞相对不透性，必须从其他 新陈代谢的前体。因此，抑制癌细胞用于维持天冬氨酸水平的机制是一种 治疗癌症的潜在方法。这项建议使用了几种方法来确定天冬氨酸水平和 确定天冬氨酸最受限制的癌症。具体地说，我们将检验以下假设 天冬氨酸是某些肿瘤的内源性代谢限制(目标1)，即还原谷氨酰胺代谢 支持低氧细胞中天冬氨酸的产生(目标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(目标3)。我们将使用细胞培养来测试机械元件 并使用临床前小鼠癌症模型来确定它们在体内的疗效。一起， 这些研究将探索针对癌细胞新陈代谢的新治疗方法，并确定 在哪些情况下它们是最好的部署。因此，该项目的长期科学目标是改进 通过确定新的治疗靶点并在癌症小鼠模型中验证它们来治疗癌症。这 职业发展奖也将对我作为科学家的发展至关重要，因为它为我提供了 在著名的马萨诸塞州理工学院科赫癌症综合研究所接受培训 技术。这段时间将用来发展我的科学思想，提高我与 最能真实再现人类疾病的癌症小鼠模型。所学到的科学进步 从这个提议和训练期将对我的最终目标建立一个独立的 研究癌细胞增殖的代谢制约因素的课题组。

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.