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.

项目概要 尽管精准医学最近取得了令人兴奋的进展，但几种常见癌症仍然难以解决 治疗包括肺癌、结直肠癌和胰腺癌，这些癌症合计超过 200,000 这些肿瘤中的一个常见分子因素是高水平的活性氧， 这会导致 DNA 氧化损伤，尤其是 8-氧鸟嘌呤 (8-OG)，它既有毒又有害 结果，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，它们可以从细胞中去除 8-OG 我们开发了控制活性的方法。 这些酶将为控制肿瘤生长提供新的、有前途的策略。 最近，还没有人能够测量或调节这些酶的活性。 在该提案的前期工作中，新颖且灵敏的化学探针已被开发出来。 设计出这是唯一可以测量 MTH1 和 OGG1 细胞活性的现有产品。 此外，这些探针已用于识别这些途径的新小分子调节剂， 令人兴奋的是，包括这两种酶的唯一已知激活剂。第三，新的假设已经出现。 关于如何通过小分子单独或联合调节这些途径的活性 组合，可以提供生物学上重要的，并且可能具有临床上有用的癌症结果。 库尔/福特合作团队将开发并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。 项目将开发新的探针来量化肿瘤细胞和组织的修复活动，以识别和修复； 开发新的小分子酶抑制剂和激活剂来测试新的生物学假设； 关于靶向上调或下调如何抑制肿瘤生长；并检验新的假设 用于预防遗传易患癌症的个体的肿瘤发生。 这项研究很重要，因为它解决了仍然存在的多种常见和致命的癌症 此外，合作团队将开发几种可能治疗的分子工具。 此外，如果成功，这项工作可能会对整个癌症研究界有所帮助。 癌症治疗的新靶向策略以及评估患者的实用方法 该研究计划在几个方面具有创新性：它将开发和应用新型分子工具。 用于评估损伤修复途径；它将导致唯一已知的小分子的开发 损伤修复的激活剂，它提出了关于如何调节修复活动的新假设 将有助于治疗甚至预防这些严重恶性肿瘤。