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

• 批准号: 8916871
• 负责人: MITCHELL J. FREDERICK
• 金额: $ 97.17万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916871
• 关键词: Biological; Biological Models; Cell Line; Cells; Computational Science; Critical Pathways; DNA Sequence Alteration; Data; Databases; Dependence; Dependency; Diffusion; Disease; Drug Interactions; Drug Targeting; Foundations; Frequencies; Genes; Genetic; Genomics; Genotype; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; In Vitro; Knowledge; Lead; Link; Malignant Neoplasms; Maps; Measures; Methods; Mining; Modeling; Molecular; Molecular Target; Mutate; Mutation; NOTCH1 gene; Oncogenes; Outcome; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Pre-Clinical Model; Sampling; Sensitivity and Specificity; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Translating; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; Xenograft Model; Xenograft procedure; base; clinically relevant; computerized tools; drug development; drug sensitivity; gene discovery; head and neck cancer patient; human disease; improved; in vivo; in vivo Model; meetings; neoplastic cell; new therapeutic target; novel; pre-clinical; public health relevance; research study; screening; therapeutic target; tumor; tumor growth

 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）：头颈部鳞状细胞癌（HNSCC）是一种使人衰弱的疾病，几乎没有基于分子的治疗方法。最近的基因组研究HNSCC已经确定了许多基因组改变，但改变是由肿瘤抑制基因和非靶向癌基因占主导地位。然而，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。我们建议联合收割机现有的基因组数据与计算方法和体内途径分析，以确定新的候选目标，在HNSCC。这些候选靶标将在具有已知基因型的HNSCC系中在高通量体内筛选系统中进行功能测试。将测试经验证的靶标的基因型共依赖性，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。目前不可药用的靶标将通过计算和实验分析其途径，以获得将进行功能测试的其他靶标。所有实验将在基因组学表征的模型中体内进行。我们的目标是为HNSCC产生一个功能验证的新靶点的广泛列表，这些靶点将成为药物开发管道的候选者。