Targeting replication stress avoidance in cancer

针对癌症中的复制应激避免

基本信息

批准号：
10608942
负责人：
Sharon B Cantor
金额：
$ 45.22万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608942
关键词：
Antineoplastic Agents Biological Assay Biological Markers Cancer cell line Cell Aging Cell Survival Cells Collection DNA DNA Damage DNA Replication Inhibition DNA biosynthesis DNA replication fork Databases Dependence Development Effectiveness Electron Microscopy Fiber Future Genes Goals Immunoblot Analysis Knowledge Lead Malignant - descriptor Malignant Neoplasms Measures Modeling Oncogenes Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Proliferating Property Proteins Proteomics Research Single-Stranded DNA Stress Structure-Activity Relationship System Testing Therapeutic addiction anti-cancer anti-cancer therapeutic biological adaptation to stress biomarker identification cancer cell cancer therapy combination cancer therapy experimental study gene synthesis genome integrity improved in vivo inhibitor insight novel preclinical study preservation prevent replication stress response scaffold screening single molecule small molecule small molecule inhibitor stress tolerance targeted cancer therapy targeted treatment tool tumor growth tumor progression tumorigenesis

项目摘要

Abstract The overall goal of this proposal is to understand and target cancer cell addictions to stress- tolerance pathways. We have discovered that cancer cells maintain proliferation by engaging in a pathway known as translesion synthesis (TLS). By employing TLS, cancer cells are able to replicate in a continuous manner and subvert the replication stress response. Here, we propose to implement state-of-the-art assays to analyze how cancer cells alter DNA replication fork dynamics and replisome components to promote TLS. By defining the core TLS machinery, we will seek to identify biomarkers and novel targets of TLS. Importantly, we have developed a small molecule inhibitor of TLS that selectively halts DNA replication in several cancer cell lines that are dependent on TLS. Moreover, we found that the colony forming potential of TLS-dependent cancer cells is dramatically reduced upon inhibition of TLS. Thus, we propose to identify the scope of TLS dependent cancers using cell screening and data base analysis. In addition, to fully further develop the therapeutic potential of TLS inhibition, we propose to measure and improve the anti- cancer potential of our lead small molecules. Collectively, these proposed studies will identify how cancer cells engage TLS and how best to block TLS to selectively target cancer.

抽象的该提案的总体目标是了解并针对癌细胞对压力耐受的成瘾途径。我们发现癌细胞通过参与称为“ 跨损伤合成（TLS）。通过采用 TLS，癌细胞能够以连续的方式复制并颠覆复制应激反应。在这里，我们建议实施最先进的检测分析癌细胞如何改变 DNA 复制叉动力学和复制体成分以促进 TLS。通过定义核心 TLS 机制，我们将寻求识别 TLS 的生物标志物和新靶点。重要的是，我们开发了一种 TLS 小分子抑制剂，可以选择性地停止 DNA 复制几种依赖 TLS 的癌细胞系。此外，我们发现菌落形成潜力抑制 TLS 后，TLS 依赖性癌细胞会显着减少。因此，我们建议确定使用细胞筛选和数据库分析确定 TLS 依赖性癌症的范围。此外，为进一步全面开发 TLS 抑制的治疗潜力，我们建议测量和提高抗癌效果我们的先导小分子的潜力。总的来说，这些拟议的研究将确定癌细胞如何参与 TLS 以及如何最好地阻止 TLS 以选择性地针对癌症。