Cancer dependencies associated with genomic alterations and targeted by small mol

癌症依赖性与基因组改变相关并通过小分子靶向

• 批准号: 8494988
• 负责人: STUART L SCHREIBER
• 金额: $ 107.26万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494988
• 关键词: Alleles; Antineoplastic Agents; BCL2 gene; Biological Markers; Cancer Biology; Cancer Patient; Cancer cell line; Caring; Categories; Cell Line; Cells; Chromatin; Clinical; Code; Collaborations; Combined Modality Therapy; Communities; Complementary DNA; Computing Methodologies; Data; Data Analyses; Data Sources; Databases; Dependency; Disease; Drug Combinations; Drug Targeting; Drug resistance; Elements; Ensure; Enzymes; Foundations; Gene Expression Alteration; Generations; Genes; Genetic; Genetic Markers; Genomics; Glucocorticoid Receptor; Health; Human; Individual; Institutes; Instruction; KRAS2 gene; Link; MEKs; Malignant Neoplasms; Measures; Medicine; Mining; Mutation; Oncogenes; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Phase; Proteins; RNA Interference; Research; Resistance; Resources; Science; Source; Sum; Testing; The Cancer Genome Atlas; War; base; cancer cell; cancer genetics; cancer genome; cancer genomics; combination cancer therapy; human FRAP1 protein; improved; inhibitor/antagonist; insight; meetings; mouse model; mutant; novel; overexpression; patient population; public health relevance; research study; resistance mechanism; response; small molecule; tool; tumor

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.

描述（由申请人提供）：靶向癌症由于特定基因组改变而获得的基于癌基因或非癌基因的依赖性的药物可产生高临床应答率，尽管该类别中的当前药物仅使一小部分癌症患者受益，并且有益应答并不总是持久的。该项目旨在发现广泛的癌症基因组改变的药物靶向依赖性，并确定可以避免或克服耐药性的药物组合。作为五中心和现在的九中心CTD 2网络的一部分，我们应用定量基因组癌症细胞系分析来构建一个交互式资源，用于识别小分子靶向的癌症遗传依赖性。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潜在混淆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。我们现在建议以增强其他网络研究和影响癌症患者健康的方式大幅推进资源。该项目将在交互式资源中整合来自基因组癌细胞系分析的小分子和RNAi数据，并发现单一药物靶向的依赖性。它还将识别和测试互动资源提出的关于小分子靶向癌症遗传依赖性的假设。最后，该项目将确定小分子药物的组合，这些药物靶向癌细胞中的癌基因或非癌基因依赖性，并避免或克服单一药物的耐药性。