权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘