P63 mediators as therapeutic targets in HNSCC

描述（由申请人提供）：本提案的目标是通过定义体内肿瘤中的p63通路，使用基因组方法鉴定头颈部鳞状细胞癌（HNSCC）的新治疗靶点。 p53家族成员p63在大多数原发性HNSCC肿瘤中过表达，并且对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亚型的小抑制RNA（siRNA）的数据表明，p63表达的丧失诱导过表达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。 到目前为止，p63的下游机制仍然很差的特点。 因此，首先将确定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同种型提供存活效应。 第二，介导p63的肿瘤相关效应的下游基因将使用HNSCC细胞中p63特异性siRNA后的表达谱来鉴定。 为了确认体内推定的p63靶点，将使用来自MGH/MEEI肿瘤库的显微切割原发性肿瘤将原发性HNSCC标本中的p63水平与全基因组表达谱相关联。 比较p63 siRNA后调控的基因与原发性肿瘤中与p63一致表达的基因，可以鉴定最具生物学相关性的p63靶点。 第三，将使用siRNA方法在HNSCC中直接测试确认的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，并将确定潜在的新的治疗靶点，介导p63在HNSCC中的关键生存效应。

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.