A Concerted Attack on Patient Specific Oncogenic Vulnerabilities in Lung Cancer

描述（由申请人提供）：肺癌是美国死亡的主要原因，显然需要额外和更好的治疗方法。很明显，有多种致癌基因型导致肺癌，这些不同的基因型对目前批准的治疗方法的反应不同。然而，这些差异的分子基础尚未被完全理解，并且尚未开展系统的方法来识别来自具有不同癌基因型的肿瘤的细胞的大多数功能差异。我们提出的工作将提供一个系统的研究，不同致癌突变的细胞对每个人类基因功能丧失的不同敏感性，揭示包含新药物靶点的途径。它将在足够大的规模上进行，以区分单个细胞系特有的遗传缺陷和存在于所有细胞中具有相同致癌基因变化的潜在治疗靶点。同时，我们将使用高通量筛选来确定一组20万种化合物中的任何一种，包括目前批准用于人类的一个子集，是否对一种或多种基因不同的肺癌亚群具有治疗益处。具有这种活性的化合物将在外植体模型中测试对人类肿瘤的活性。这将为新疗法提供潜在的快速通道，以及检测抗RNAi策略检测的肿瘤特异性脆弱性的方法。结合功能基因组和化合物筛选结果的数据库将通过将其连接到caGRID并将化合物结构和链接的生物学数据上传到PubChem向公众开放。

DESCRIPTION (provided by applicant): Lung cancer is a major cause of death in the United States and there is a clear need for additional and better therapeutic approaches to its treatment. It is clear that there are multiple oncogenotypes that cause lung cancer and that these different genotypes respond differently to currently approved therapeutics. However, the molecular basis of these differences are not understood completely and a systematic approach to identifying most of the functional differences in cells derived from tumors having different oncogenotypes has not been carried out. The work we propose will provide a systematic study of differential sensitivities of cells with different oncogenic mutations to the loss of function of each human gene, revealing pathways that contain novel drug targets. It will be conducted on a scale large enough to distinguish genetic weaknesses that are specific for a single cell line from potential therapeutic targets that are present in all cells sharing the same set of oncogenic genetic changes. In parallel, we will use high-throughput screening to determine if any of a set of 200,000 compounds, including a subset currently approved for use in humans, has therapeutic benefit in one or more subsets of genetically distinct lung cancer. Compounds that have such activity will be tested for activity against human tumors in explant models. This will provide a potential fast-track for novel therapies as well as a method for detecting tumor specific vulnerabilities that are resistant to detection by RNAi strategies. A database of the combined functional genomic and compound screening results will be made available to the public by linking it to caGRID and uploading compound structures and linked biological data to PubChem. PUBLIC HEALTH RELEVANCE: This project will test the hypothesis that cell lines derived from human lung cancers can be used to identify therapeutic targets, and leads for therapeutic drugs, that are shared by tumors that have a similar gene expression signature. The project will produce a large database that can be used by researchers to design patient-specific, individualized therapies for lung cancer.