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Measuring and Modulating Oxidative DNA Damage Surveillance Pathways

测量和调节氧化 DNA 损伤监测途径

基本信息

批准号：
9287818
负责人：
ERIC T. KOOL
金额：
$ 43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9287818
关键词：
8-hydroxyguanosine Address Affect Basic Science Biological Biological Assay Cell Line Cells Cessation of life Chemicals Clinical Colorectal Cancer Communities DNA Development Disease Down-Regulation Drug Industry Enzyme Activators Enzymes Fluorescence Growth and Development function Guanine Health Human Immunotherapy Individual Lead Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measures Methods Modeling Molecular Molecular Probes Mutagenesis Nucleotides OGG1 gene Outcome Pathway interactions Patients Prevention Reactive Oxygen Species Reporter Research Research Personnel Role Specimen System Testing Tissues Toxic effect Tumor Cell Line Tumor Tissue Work anticancer research cancer therapy combat design enzyme activity inhibitor/antagonist innovation neoplastic cell novel oxidation oxidative DNA damage oxidative damage precision medicine prevent rapid growth repaired scaffold screening small molecule small molecule inhibitor tool tumor tumor growth tumorigenesis

项目摘要

Project Summary Despite exciting progress made recently in precision medicine, several common cancers remain difficult to treat, including lung, colorectal, and pancreatic cancer, which together account for over 200,000 deaths annually. One common molecular factor in these tumors is high levels of reactive oxygen species, which lead to oxidative damage in DNA – most notably, 8-oxoguanine (8-OG), which is both toxic and mutagenic. As a result, tumor cells evolve strategies to support rapid growth, and thus often misregulate the enzymes that combat this damage: namely MTH1 and OGG1, which remove 8-OG from the nucleotide pool and from DNA itself. We hypothesize that developing approaches to control the activities of these enzymes will provide new and promising strategies for controlling tumor growth. However, until very recently no one has been able to measure or modulate these enzymes' activities. In preliminary work leading up to this proposal, novel and sensitive chemical probes have been devised that are the only existing reporters that can measure the cellular activities of MTH1 and OGG1. In addition, these probes have been used to identify new small-molecule modulators of these pathways, including, excitingly, the only known activators of the two enzymes. Third, new hypotheses have been developed regarding how modulating the activities of these pathways via small molecules, singly or in combination, can provide biologically important, and potentially clinically useful, outcomes in cancer. The Kool/Ford collaborative team will develop and employ these molecular tools to investigate the promise of modulating these important repair pathways. The specific aims for the four-year term of the project are to develop new probes to quantify repair activities in tumor cells and tissues; to identify and develop new small-molecule inhibitors and activators of the enzymes; to test novel biological hypotheses regarding how targeted up- or down-regulation may suppress tumor growth; and to test a new hypothesis for preventing tumorigenesis in individuals who are genetically susceptible to developing cancer. This research is important because it addresses multiple common and deadly cancers that remain difficult to treat. In addition, the collaborative team will develop several molecular tools that are likely to be useful to the cancer research community as a whole. Moreover, if successful, this work may lead to new targeted strategies for cancer treatment, and practical methods for evaluating patients for these therapies. This research plan is innovative in several ways: it will develop and apply novel molecular tools for assessing damage repair pathways; it will lead to the development of the only known small-molecule activators of damage repair, and it presents new hypotheses regarding how modulating repair activities will be helpful in treatment - and even prevention - of these serious malignancies.

项目总结