Investigating Mechanisms of Deregulated Nucleotide Metabolism in Cancer

研究癌症中核苷酸代谢失调的机制

基本信息

批准号：
10452714
负责人：
Tom Cunningham
金额：
$ 36.71万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452714
关键词：
Affect Amino Acid Substitution Anabolism Apoptosis B-Lymphocytes Biochemical Biochemistry CRISPR/Cas technology Cancer Model Cancer cell line Cell Lineage Cell Proliferation Cell Survival Cells Chemistry Chimerism Complex Cre-LoxP Cytosol Cytotoxic Chemotherapy DNA Polymerase I DNA Polymerase II DNA Polymerase III DNA-Directed RNA Polymerase Data Dependence Development Diphosphates Economics Enzymatic Biochemistry Enzymes Feedback Foundations Future Gene Expression Genetic Genetic Transcription Genetically Engineered Mouse Growth Hematopoietic Homo Homologous Gene Human Immunologics Individual Intelligence Knockout Mice Lead Lesion Link Lymphoma Lymphomagenesis MYC gene Malignant Neoplasms Metabolic Metabolism Microscopy Modeling Molecular Molecular Biology Multienzyme Complexes Multiple Myeloma Mus Natural regeneration Normal Cell Normal tissue morphology Nucleic Acids Nucleotide Biosynthesis Nucleotides Oncogenic Output Pathway interactions Patients Pentosephosphate Pathway Phenotype Physiology Production Proliferating Property Purines Pyrimidine RNA chemical synthesis Refractory Research Resolution Ribose Ribose-Phosphate Pyrophosphokinase Role Route Stable Isotope Labeling Structural Models Structure Testing Therapeutic Tissues Toxic effect Work anti-cancer base c-myc Genes cancer cell cytotoxic design enzyme activity genetic approach inorganic phosphate liquid chromatography mass spectrometry loss of function mouse model mutant next generation novel nucleic acid biosynthesis nucleotide metabolism overexpression programs pyridine rational design single molecule stoichiometry therapeutically effective tumor tumor metabolism

项目摘要

PROJECT SUMMARY Many cancers are currently treated by cytotoxic chemotherapies that exploit those cancers' dependence on enhanced nucleotide biosynthesis. However, the cytotoxic properties which make these compounds so efficacious in killing cancer cells also wreak havoc on normal proliferating cells and tissues. In order to understand how to exploit this vulnerability more effectively and more safely, we must focus our efforts on targets that are specifically required by cancer cell, but not normal cell, proliferation and survival. My discoveries have identified one such target – the enzyme phosphoribosyl pyrophosphate synthetase 2 (PRPS2). PRPS2, and its homolog PRPS1, generate a critical precursor necessary for producing all nucleotides and function as a `molecular throttle' capable of increasing or decreasing the rate at which these genetic building blocks are made. This proposal seeks to unravel the molecular basis for this selectivity through use of metabolic flux analysis, elegant structure/function studies, and bioorthogonal chemistry and molecular biology approaches. Our studies will open up new avenues for understanding the metabolic vulnerabilities of cancer cells and may lead to intelligently-designed rational therapeutic strategies of the future. We will conduct our studies using models of MYC-driven lymphoma and myeloma, using both genetically- engineered mouse models and human cancer cell lines. Importantly, MYC has been characterized as the transcriptional engine of cancer and its ability to stimulate nucleotide and nucleic acid production are signature features of its pro-growth anabolic program necessary to drive malignancies in the B cell lineage. Using our genetic approaches that block PRPS2 function in MYC overexpressing cells, we can leverage this dependency to decipher the mechanistic basis for the deregulation of nucleotide metabolism in MYC-overexpressing cancer cells and uncover novel connections between critical nodes in the nucleotide metabolism network. For example, our proposed studies will elucidate the economics of nucleotide metabolism by determining how disrupting nucleotide supply affects the machineries it fuels, and vice-versa. Collectively, the proposed studies will be transformative in our understanding of the roles of these key molecules in the normal and cancer setting, and provide a new conceptual paradigm which can be the foundation for the development of the next generation of safer, more effective precision-based therapies and approaches.

项目概要目前，许多癌症通过细胞毒性化疗来治疗，这些化疗利用了这些癌症对然而，这些化合物的细胞毒性特性使得核苷酸生物合成增强。有效杀死癌细胞的同时也会对正常增殖的细胞和组织造成严重破坏。了解如何更有效、更安全地利用此漏洞，我们必须集中精力癌细胞（而非正常细胞）增殖和存活特别需要的靶标。发现已经确定了这样一个目标——磷酸核糖焦磷酸合成酶 2 (PRPS2) 及其同源物 PRPS1，生成产生所有必需的关键前体。核苷酸并起到“分子节流阀”的作用，能够增加或减少这些物质的速率该提议旨在揭示这种选择性的分子基础。通过使用代谢流分析、优雅的结构/功能研究和生物正交化学和我们的研究将为理解代谢开辟新的途径。癌细胞的脆弱性，可能会导致未来智能设计的合理治疗策略。我们将使用 MYC 驱动的淋巴瘤和骨髓瘤模型进行研究，同时使用遗传- 重要的是，MYC 已被定性为工程小鼠模型和人类癌细胞系。癌症的转录引擎及其刺激核苷酸和核酸产生的能力是标志其促生长合成代谢程序的特征是驱动 B 细胞谱系恶性肿瘤所必需的。阻止 MYC 过表达细胞中 PRPS2 功能的遗传方法，我们可以利用这种依赖性破译 MYC 过表达癌症中核苷酸代谢失调的机制基础细胞并揭示核苷酸代谢网络中关键节点之间的新连接。例如，我们提出的研究将通过确定如何进行核苷酸代谢来阐明核苷酸代谢的经济学扰乱核苷酸供应会影响其提供燃料的机器，反之亦然。将彻底改变我们对这些关键分子在正常和癌症中的作用的理解设定，并提供一个新的概念范式，可以为下一步的发展奠定基础产生更安全、更有效的精准疗法和方法。