Translating genomic alterations into novel therapeutic targets in head and neck cancer through computational and functional approaches

 描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是一种衰弱的疾病，几乎没有基于分子的治疗方法。最近对HNSCC的基因组研究发现了大量的基因组改变，但这些改变主要是由肿瘤抑制基因和不可靶向的癌基因主导的。然而，我们假设在HNSCC中存在新的分子治疗靶点，并且这些靶点存在于尚未有效分析的部分数据中。我们建议将现有的基因组数据与计算方法和体内通路分析相结合，以确定HNSCC中的新候选靶点。这些候选靶点将在高通量体内筛选系统中进行功能测试，这些筛选系统将在具有已知基因的HNSCC株中进行。验证的靶点将被测试基因相关性，任何已知的药物靶点将在临床前异种移植模型中进行测试。目前不能下药的目标将通过计算和实验分析其路径，以获得更多将进行功能测试的目标。所有的实验都将在体内的基因组模型中进行。我们的目标是为HNSCC生成一个广泛的功能验证的新靶点清单，这些靶点将成为药物开发流水线的候选者。

 DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease with few molecularly-based therapeutics. Recent genomic studies of HNSCC have identified numerous genomic alterations, but the alterations are dominated by tumor suppressor genes and untargetable oncogenes. Nevertheless, we hypothesize that novel molecular therapeutic targets are present in HNSCC and that these targets exist in parts of the data that have not been effectively analyzed. We propose to combine existing genomic data with computational approaches and in vivo pathway analysis to identify novel candidate targets in HNSCC. These candidate targets will be functionally tested in a high-throughput in vivo screening system in HNSCC lines with known genotype. Validated targets will be tested for genotype co-dependencies, and any known drug targets will be tested in preclinical xenograft models. Targets that are not currently druggable will have their pathways computationally and experimentally analyzed for additional targets that will be functionally tested. All experiments wil be performed in vivo in genomically characterized models. We aim to generate an extensive list of functionally validated novel targets for HNSCC that will be candidates for drug development pipelines.