Cancer dependencies associated with genomic alterations and targeted by small mol

描述(申请人提供)：针对癌症因特定基因组改变而获得的癌基因或非癌基因依赖的药物可以产生高临床应答率，尽管目前这类药物只对一小部分癌症患者有效，而且有益的反应并不总是持久的。该项目旨在发现一系列癌症基因组改变的药物靶向依赖关系，并确定可以避免或克服耐药性的药物组合。作为五个中心和现在的九个中心CTD2网络的一部分，我们应用定量基因组癌细胞系图谱来构建一个互动资源，用于识别小分子靶向的癌症遗传相关性。我们通过公共数据库、交互式数据分析工具、代码和指导用户解决可能令人困惑的数据分析问题的说明，向癌症社区提供了这一资源的所有方面。我们现在建议大幅提高资源，以加强其他网络研究并影响癌症患者的健康。该项目将在互动资源中整合来自基因组癌细胞系图谱的小分子和RNAi数据，并发现单个代理所针对的依赖关系。它还将识别和测试互动资源提出的关于以小分子为靶标的癌症遗传相关性的假设。最后，该项目将确定小分子药物的组合，这些药物针对癌细胞中的癌基因或非癌基因依赖，并避免或克服单一药物的耐药性。

DESCRIPTION (provided by applicant): Drugs that target oncogene- or non-oncogene-based dependencies acquired by cancers as a result of specific genomic alterations can yield high clinical response rates, although current drugs in this category benefit only a small fraction of cancer patients and the beneficial responses are not always durable. This project aims to discover drug-targetable dependencies for a wide range of cancer genomic alterations and identify the combinations of drugs that can avoid or overcome resistance. As part of the five-center and now nine-center CTD2 Network, we applied quantitative genomic cancer cell-line profiling to build an interactive resource for identifying cancer genetic dependencies targeted by small molecules. We made all aspects of this resource available to the cancer community through a public database, interactive data-analysis tools, code, and instructions that guide users through potentially confounding data- analysis issues. We now propose to advance the resource substantially in ways that enhance other Network research and impact the health of cancer patients. The project will integrate small-molecule and RNAi data from genomic cancer cell-line profiling within the interactive resource and discover dependencies targeted by single agents. It will also identify and test hypotheses suggested by the interactive resource about cancer genetic dependencies targeted by small molecules. Finally, the project will identify combinations of small- molecule agents that target oncogene or non-oncogene dependencies in cancer cells and that avoid or overcome drug resistance seen with single agents.