Measuring and Modulating DNA Damage Surveillance Pathways

测量和调节 DNA 损伤监测途径

• 批准号: 10396578
• 负责人: ERIC T. KOOL
• 金额: $ 46.78万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396578
• 关键词: Address; Affect; Animal Disease Models; Basic Science; Biological; Biological Assay; Biological Models; Biological Testing; Cancer Etiology; Cancer Patient; Cell Culture Techniques; Cell Line; Cell model; Cells; Cessation of life; Chemicals; Chemoprevention; Clinical; Clinical Research; Colorectal Cancer; Communities; Cytosine; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Sequence Alteration; Deamination; Development; Diagnosis; Disease; Drug resistance; Enzymes; Genes; Genetic Predisposition to Disease; Growth; Heart; High-Risk Cancer; Image; Incidence; Inflammation; Inflammatory; Intestines; Lead; Malignant Neoplasms; Measures; Molecular; Molecular Target; Mus; Mutagenesis; Mutation; Neoplasm Metastasis; OGG1 gene; Outcome; Pathway interactions; Patients; Persons; Point Mutation; Population; Populations at Risk; Prevention; Reporter; Research; Research Personnel; Risk; Solid Neoplasm; Source; Specimen; Syndrome; Testing; Tissues; Work; adverse outcome; anticancer research; base; brca gene; cancer drug resistance; cancer prevention; cancer therapy; clinically relevant; enzyme activity; experience; high risk; innovation; malignant breast neoplasm; mouse model; novel; oxidative damage; polyposis; precision medicine; prevent; repair enzyme; repaired; small molecule; tool; tumor; tumorigenesis; whole genome

The formation of mutations in cellular DNA lies at the heart of cancer and its treatment. Patients diagnosed with the deadliest solid tumors undergo treatment based on the alterations of DNA sequence in their cancer, and further mutations that occur during treatment cause all-too-common adverse outcomes, including the emergence of drug resistance and metastasis. Of course, these DNA alterations are responsible for the genesis of malignancies in the first place, as accumulated mutations in driver genes lead to uncontrolled growth. Strategies for suppressing mutagenesis can be important for preventing cancer in at-risk populations, and for limiting the emergence of drug resistance and metastasis in existing cancer patients. Here we propose to test a new, molecularly targeted approach to agents that suppress this adverse mutagenesis. Our strategy is based on the most common molecular origins of these cancers: namely, point mutations that arise from specific forms of DNA damage. Our specific aims for the four-year term of the project are to develop new probes to quantify DNA damage in cells and tissues; to identify and develop new small- molecule activators of the repair enzymes that repair the most common sources of mutations; to test whether upregulating DNA repair can suppress the emergence of cancer drug resistance; and to test whether we can lower the incidence of cancer in tumor-prone mice. In progress leading up to this proposal, we have devised several novel and sensitive chemical probes as first-in-class reporters that can measure the cellular activities of multiple DNA repair enzymes. We have employed these probes in clinically relevant studies of cell and tumor specimens, and in investigating connections between inflammation and DNA repair in animal models of disease. In addition, we have used these probes to develop new small-molecule modulators of these pathways, including, excitingly, the only known activators of some of these enzymes. Putting our experience together, we have developed new hypotheses regarding how upregulating the activities of these pathways via small molecules can provide biologically important, and potentially clinically useful, outcomes in cancer. This research is important because it addresses the possibility of preventing common and deadly cancers that remain difficult to treat. In addition, our team will develop molecular tools, including probes, assays, and cell lines, that are likely to be useful to the cancer research community as a whole. Our research plan is innovative in several ways: it will develop and apply new molecular tools for assessing damage and repair pathways; it will lead to the development of the first small-molecule activators of multiple repair enzymes; and it tests new hypotheses regarding how modulating repair activities will be helpful in treatment - and even prevention - of these serious malignancies.

细胞DNA中突变的形成在于癌症的核心及其治疗。患者被诊断出 最致命的实体瘤基于癌症中DNA序列的改变，接受治疗， 在治疗过程中发生的进一步突变会导致非常普遍的不良结果，包括 耐药性和转移的出现。当然，这些DNA改变是造成的 首先是恶性肿瘤的起源，因为驱动基因的累积突变导致不受控制 生长。抑制诱变的策略对于预防高危人群的癌症很重要， 并限制现有癌症患者的耐药性和转移的出现。 在这里，我们建议测试一种针对抑制这种不利的代理的新的，分子的靶向方法 诱变。我们的策略基于这些癌症最常见的分子起源：即 由特定形式的DNA损伤引起的突变。我们对项目四年期任期的具体目标 要开发新的探针来量化细胞和组织中的DNA损伤；识别和开发新的小型 修复最常见的突变来源的修复酶的分子激活剂；测试是否 上调DNA修复可以抑制癌症耐药性的出现；并测试我们是否可以 降低容易发生肿瘤小鼠的癌症的发生率。 在此提案之前，我们设计了几种新颖而敏感的化学探针为 可以测量多个DNA修复酶的细胞活性的一流记者。我们有 在细胞和肿瘤标本的临床相关研究中使用了这些探针，并在研究 疾病动物模型的炎症与DNA修复之间的联系。此外，我们已经使用了 这些探针开发了这些途径的新小分子调节剂，包括，令人兴奋的是唯一的 其中一些酶的已知激活剂。将我们的经验融合在一起，我们开发了新的 关于通过小分子上调这些途径活动的假设可以提供 生物学上重要的且潜在的临床有用的癌症结果。 这项研究很重要，因为它解决了预防常见和致命癌症的可能性 那仍然很难治疗。此外，我们的团队将开发分子工具，包括探针，测定和 细胞系可能对整个癌症研究界有用。我们的研究计划是 以几种方式创新：它将开发和应用新的分子工具来评估损坏和维修 途径；它将导致多种修复酶的第一个小分子激活剂的发展；和 它检验了有关调节维修活动如何有助于治疗的新假设，甚至 预防 - 这些严重的恶性肿瘤。