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.

项目摘要/摘要与出现的正常组织相比，癌症显示出改变的细胞代谢。一有希望的治疗方法是通过设计针对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核苷酸的合成和所需的蛋白质的合成，对癌细胞增殖至关重要增殖。重要的是，初步数据表明，细胞内天冬氨酸是内源性代谢肿瘤生长的限制。天冬氨酸相对不渗透细胞，必须从其他代谢前体。因此，抑制癌细胞用来维持天冬氨酸水平的机制是治疗癌症的潜在方法。该建议使用几种方法来针对天冬氨酸水平，确定天冬氨酸最有限的癌症。具体来说，我们将检验天冬氨酸是某些肿瘤的内源代谢限制（AIM 1），是还原性谷氨酰胺代谢支持低氧细胞中天冬氨酸的生产（AIM 2），并且大天候合成的改变会影响天冬氨酸水平和癌细胞增殖（AIM 3）。我们将使用细胞培养来测试机械元素在这些假设中，并使用癌症的临床前小鼠模型来确定其体内功效。一起，这些研究将研究针对癌细胞代谢的新的治疗方法，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改善通过鉴定新的治疗靶标并在癌症的小鼠模型中验证癌症治疗。这职业发展奖对于我作为科学家的发展也将至关重要马萨诸塞州科赫综合癌症研究所的培训期技术。这次将被用来发展我的科学思想并提高我与之合作的能力最忠实地概括人类疾病的癌症小鼠模型。科学进步学到了根据该提案和培训期，对于我建立独立的最终目标至关重要研究研究小组研究了癌细胞增殖的代谢约束。