Measuring and Modulating Oxidative DNA Damage Surveillance Pathways

项目摘要 尽管最近在精准医学方面取得了令人兴奋的进展，但几种常见的癌症仍然很难治疗。 治疗，包括肺癌，结肠直肠癌和胰腺癌，这些癌症加起来超过20万， 每年死亡。这些肿瘤中的一个常见分子因素是高水平的活性氧， 导致DNA的氧化损伤-最值得注意的是8-氧代鸟嘌呤（8-OG），它既有毒， 致突变的结果，肿瘤细胞进化出支持快速生长的策略，因此经常发生失调 对抗这种损伤的酶：即MTH 1和OGG 1，它们从细胞中去除8-OG。 核苷酸库和DNA本身。我们假设，开发控制活动的方法 这些酶的研究将为控制肿瘤生长提供新的和有前途的策略。然而直到 最近还没有人能够测量或调节这些酶的活性。 在导致这一提议的初步工作中，已经研究了新颖且灵敏的化学探针。 设计的是唯一现有的可以测量MTH 1和OGG 1的细胞活性的报告基因。 此外，这些探针已被用于鉴定这些途径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 关于如何调节这些途径的活动，通过小分子，单独或在 组合可以在癌症中提供生物学上重要的和潜在的临床上有用的结果。 库尔/福特合作团队将开发和使用这些分子工具来研究 调节这些重要的修复途径的承诺。四年任期的具体目标是： 项目是开发新的探针，以量化肿瘤细胞和组织中的修复活动;识别和 开发新的酶的小分子抑制剂和激活剂;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;并测试一个新的假设 用于预防遗传上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，合作小组将开发几种分子工具， 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 癌症治疗的新靶向策略，以及评估这些患者的实用方法 治疗这项研究计划在几个方面具有创新性：它将开发和应用新颖的分子工具 用于评估损伤修复途径;它将导致开发出唯一已知的小分子 激活剂的损伤修复，它提出了新的假设，关于如何调节修复活动 将有助于治疗甚至预防这些严重的恶性肿瘤。

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.