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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：
10671540
负责人：
Tom Cunningham
金额：
$ 35.98万
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/10671540
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 Induction of Apoptosis Intelligence Knockout Mice Lesion Ligase Link Lymphoma Lymphomagenesis MYC gene Malignant Neoplasms Metabolic Metabolism 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 Ribose Ribose-Phosphate Pyrophosphokinase Role Route Stable Isotope Labeling Structural Models Structure Testing Therapeutic Tissues Toxic effect Work anti-cancer c-myc Genes cancer cell cytotoxic design enzyme activity genetic approach human cancer mouse model 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 superresolution microscopy synergism 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.

项目总结