Measuring and Modulating Oxidative DNA Damage Surveillance Pathways

测量和调节氧化 DNA 损伤监测途径

• 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
• 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

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.

项目摘要 尽管精准医学最近取得了令人振奋的进展，但几种常见的癌症仍然难以治愈。 治疗，包括肺癌，结直肠癌和胰腺癌，加起来超过20万 每年的死亡人数。这些肿瘤的一个共同的分子因素是高水平的活性氧物种， 这会导致DNA的氧化损伤--最著名的是8-氧鸟嘌呤(8-OG)，它是有毒的和 致突变性。其结果是，肿瘤细胞进化出支持快速生长的策略，因此经常发生错误调节。 对抗这种损伤的酶：即MTH1和OGG1，它们从细胞中去除8-OG 核糖核酸库和DNA本身。我们假设，制定控制这些活动的方法 这些酶将为控制肿瘤生长提供新的和有希望的策略。然而，直到 最近，还没有人能够测量或调节这些酶的活性。 在这项提议之前的初步工作中，新的和灵敏的化学探针 这是现有的唯一可以测量MTH1和OGG1细胞活动的记者。 此外，这些探针还被用来识别这些通路的新的小分子调节剂， 令人兴奋的是，包括这两种酶唯一已知的激活剂。第三，新的假设是 关于如何通过小分子调节这些通路的活动而开发的，单个或 联合应用，可为癌症患者提供具有重要生物学意义和潜在临床应用价值的治疗结果。 Kool/Ford合作团队将开发和使用这些分子工具来研究 承诺调节这些重要的修复途径。四年任期的具体目标是 项目是开发新的探针来量化肿瘤细胞和组织的修复活动；识别和 开发新的小分子酶抑制剂和激活剂；测试新的生物假说 关于定向上调或下调如何抑制肿瘤生长；以及检验一个新的假说 用于预防在遗传上易患癌症的人发生肿瘤。 这项研究很重要，因为它解决了多种常见和致命的癌症 很难治疗。此外，合作团队将开发几种分子工具，这些工具很可能 对整个癌症研究界都是有用的。此外，如果成功，这项工作可能会导致 癌症治疗的新的有针对性的策略，以及评估患者的实用方法 治疗。这项研究计划在几个方面具有创新性：它将开发和应用新的分子工具 用于评估损伤修复途径；它将导致唯一已知的小分子的发展 损伤修复的激活剂，并提出了关于如何调节修复活动的新假说 将有助于治疗-甚至预防-这些严重的恶性肿瘤。