P63 mediators as therapeutic targets in HNSCC

P63 介质作为 HNSCC 的治疗靶点

• 批准号: 7028347
• 负责人: LEIF W ELLISEN
• 金额: $ 38.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028347
• 关键词: apoptosis; carcinogenesis; cell line; gene expression; gene expression profiling; head /neck neoplasm; human tissue; laser capture microdissection; microarray technology; neoplasm /cancer genetics; neoplastic process; p53 gene /protein; polymerase chain reaction; protein isoforms; protein reconstitution; protein structure function; small interfering RNA; squamous cell carcinoma; transcription factor; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): The goal of this proposal is to use genomic approaches to identify new therapeutic targets for head and neck squamous cell carcinoma (HNSCC), by defining the p63 pathway in tumors in vivo. The p53 family member p63 is overexpressed in a majority of primary HNSCC tumors and is essential for epithelial precursor development in vivo, suggesting a role for this gene in tumorigenesis. Our recent data using small inhibitory RNA (siRNA) targeted against specific p63 isoforms demonstrates that loss of p63 expression induces apoptosis in HNSCC cells that overexpress p63. In contrast, p63 inhibition has no effect on survival of normal keratinocytes or of tumor cells that do not express p63. To date, the downstream mechanisms of p63 remain poorly characterized. Therefore it will first be determined whether death following p63 inhibition depends on intact function of p53 or the related gene p73, and which p63 isoform(s) provide the survival effect. Second, the downstream genes that mediate tumor-associated effects of p63 will be identified using expression profiling following p63-specific siRNA in HNSCC cells. To confirm putative p63 targets in vivo, microdissected primary tumors from the MGH/MEEI tumor bank will be used to correlate p63 levels with genome-wide expression profiles in primary HNSCC specimens. Comparison of genes regulated following p63 siRNA to genes expressed coincident with p63 in primary tumors should allow identification of the most biologically relevant p63 targets. Third, the potential therapeutic relevance of the confirmed p63 targets will be tested directly in HNSCC using an siRNA approach. Together these studies will define the relevance of the p63 pathway in tumorigenesis, and will identify potential new therapeutic targets that mediate the critical survival effect of p63 in HNSCC.

描述（由申请人提供）：该提案的目标是通过定义体内肿瘤中的 p63 通路，使用基因组方法来确定头颈鳞状细胞癌 (HNSCC) 的新治疗靶点。 p53 家族成员 p63 在大多数原发性 HNSCC 肿瘤中过度表达，并且对于体内上皮前体发育至关重要，表明该基因在肿瘤发生中的作用。 我们最近使用针对特定 p63 同工型的小抑制性 RNA (siRNA) 的数据表明，p63 表达缺失会诱导过度表达 p63 的 HNSCC 细胞凋亡。 相反，p63 抑制对正常角质形成细胞或不表达 p63 的肿瘤细胞的存活没有影响。 迄今为止，p63 的下游机制仍知之甚少。 因此，首先要确定p63抑制后的死亡是否取决于p53或相关基因p73的完整功能，以及哪种p63亚型提供了存活效应。 其次，将使用 HNSCC 细胞中 p63 特异性 siRNA 的表达谱来鉴定介导 p63 肿瘤相关效应的下游基因。 为了确认体内假定的 p63 靶点，来自 MGH/MEEI 肿瘤库的显微解剖原发性肿瘤将用于将 p63 水平与原发性 HNSCC 标本中的全基因组表达谱相关联。 将 p63 siRNA 调控的基因与原发性肿瘤中与 p63 一致表达的基因进行比较，应该能够鉴定出生物学上最相关的 p63 靶标。 第三，将使用 siRNA 方法直接在 HNSCC 中测试已确认的 p63 靶点的潜在治疗相关性。 这些研究将共同​​确定 p63 通路在肿瘤发生中的相关性，并将确定介导 p63 在 HNSCC 中关键生存作用的潜在新治疗靶点。