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

通过计算和功能方法将基因组改变转化为头颈癌的新治疗靶点

基本信息

批准号：
9475562
负责人：
MITCHELL J. FREDERICK
金额：
$ 95.7万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2021-04-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：头颈鳞状细胞癌（HNSCC）是一种使人衰弱的疾病，几乎没有基于分子的治疗方法。最近的 HNSCC 基因组研究发现了许多基因组改变，但这些改变主要是抑癌基因和不可靶向的癌基因。尽管如此，我们假设 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途径分析相结合，以确定 HNSCC 中的新候选靶标。这些候选靶标将在高通量体内筛选系统中在已知基因型的 HNSCC 系中进行功能测试。将测试经过验证的靶标的基因型相互依赖性，并且将在临床前异种移植模型中测试任何已知的药物靶标。目前不可成药的靶标将对其路径进行计算和实验分析，以寻找将进行功能测试的其他靶标。所有实验都将在体内基因组特征模型中进行。我们的目标是生成一份经过功能验证的 HNSCC 新靶点的广泛列表，这些靶点将成为药物开发管道的候选靶点。