Metabolic Constraints on Cancer Cell Proliferation

癌细胞增殖的代谢限制

基本信息

批准号：
10062482
负责人：
Lucas Bryan Sullivan
金额：
$ 34.75万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062482
关键词：
Address Affect Alleles Amino Acids Animal Model Asparagine Aspartate Aspartate-Ammonia Ligase Cancer Model Cavia Cell Culture Techniques Cell Hypoxia Cell Proliferation Cells Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Competence Consumption Data Development Dose Elements Environment Enzymes Fatty Acids Fatty acid glycerol esters Genetic Glutamine Goals Growth Human Hypoxia Implant Institutes Isocitrate Dehydrogenase K-Series Research Career Programs Lipids Location Malignant Neoplasms Mass Fragmentography Massachusetts Measurement Measures Mentors Metabolic Metabolic Pathway Metabolism Methods Mitochondria Modeling Mus Natural regeneration Normal Cell Normal tissue morphology Oxaloacetates Oxidants Oxygen Pathway interactions Permeability Pharmacology Physiological Production Proliferating Protein Biosynthesis Recombinants Research Respiration Scientific Advances and Accomplishments Scientist Source Technology Testing Therapeutic Time Tissues Training anticancer research asparaginase cancer cell cancer therapy carboxylation cofactor extracellular human disease improved in vivo insight metabolic abnormality assessment mouse model new therapeutic target novel therapeutic intervention novel therapeutics nucleotide metabolism pre-clinical stable isotope therapy design tissue culture tool tumor tumor growth tumor metabolism

项目摘要

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.

项目概要/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。一有前途的治疗方法是通过设计针对目标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所需核苷酸和蛋白质的合成，对癌细胞增殖至关重要增殖。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肿瘤生长的限制。天冬氨酸对细胞相对来说是不可渗透的，必须从其他物质合成代谢前体。因此，抑制癌细胞维持天冬氨酸水平的机制是一种治疗癌症的潜在方法。该提案使用多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。具体来说，我们将测试以下假设：天冬氨酸是某些肿瘤的内源性代谢限制（目标 1），可减少谷氨酰胺代谢支持缺氧细胞中天冬氨酸的产生（目标 2），并且改变天冬酰胺合成会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这些假设并使用临床前癌症小鼠模型来确定它们的体内功效。一起，这些研究将调查针对癌细胞代谢的新治疗方法，并确定最好部署它们的情况。因此，该项目的长期科学目标是提高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。这职业发展奖为我提供指导，对我作为一名科学家的发展也至关重要在著名的麻省理工学院科赫综合癌症研究所接受培训技术。这段时间将用于发展我的科学思想并提高我与他人合作的能力最忠实地再现人类疾病的小鼠癌症模型。学到的科学进步从这个建议来看，培训时间对于我建立独立的最终目标至关重要研究小组研究癌细胞增殖的代谢限制。