P63 Mechanisms and mediators in HNSCC

项目摘要 该项目的长期目标是确定新的、更有效的、毒性更小的治疗方法。 和颈部鳞状细胞癌（HNSCC）和相关癌症，通过了解功能和 p53家族成员p63和p73的调节。p53蛋白家族在肿瘤的发生发展中起着关键作用。 HNSCC的发病机制。p53基因本身是大多数这些突变失活的靶点。 肿瘤和p53突变型肿瘤是高度致命的，与治疗方式无关。相反，相关 家族成员p63未突变，但显著过表达和/或经历基因组扩增 在大多数情况下。P63是正常上皮细胞发育的一个谱系特异性主调节因子， 以及其他已经证明在控制增殖、分化、分化和/或分化的途径的连接处起作用的基因。 和HNSCC中恶性上皮细胞的存活。通过建立HNSCC的生理小鼠模型， 我们证明了这些肿瘤依赖于高水平的p63，它严重激活了旁分泌， FGFR信号轴是肿瘤细胞存活所必需的。这些的生理意义 p63/p73是细胞凋亡的直接介导者， HNSCC的化疗敏感性被Bcl-2上调所消除，Bcl-2是治疗抗性的介导物。 HNSCC在肿瘤区室中表现出广泛的细胞异质性， 必须针对维持肿瘤自我更新能力的再生群体。这里我们 描述了一种由p63介导的驱动再生增殖的新的和强大的转录程序 在HNSCC。在目标1中，我们将进行体内研究，以证实一个关键的p63相关辅因子， 再生程序所需的，测试对染色质的影响，并确定下游转录 功能性贡献。在目标2中，我们将验证额外的p63相关辅因子， 药理学靶点，我们假设它介导与肿瘤相关的中心转录程序 进展在目标3中，我们描述了患者样本的分子分析和体外药物筛选， 我们发现了一种治疗铂耐药HNSCC的新方法， 致癌和MAP激酶途径。我们将通过采用遗传模型、临床 药理学抑制剂，以及对参加早期临床试验的患者进行的相关组织研究。在 除了提高我们对HNSCC基础生物学的认识外，这些研究还将推进以下目标： 发现新的和可行的治疗靶点，以改善这种疾病的治疗结果。

PROJECT SUMMARY The long-term objective of this project is to identify new, more effective, and less toxic therapies for Head and Neck Squamous Cell Carcinoma (HNSCC) and related cancers, by understanding the function and regulation of the p53 family members p63 and p73. The p53 family of proteins plays a key role in the pathogenesis of HNSCC. The p53 gene itself is a target of mutational inactivation in the majority of these tumors, and p53-mutant tumors are highly lethal regardless of treatment modality. In contrast, the related family member p63 is not mutated but is dramatically overexpressed and/or subject to genomic amplification in the majority of cases. P63 is a lineage-specific master regulator of normal epithelial development that we and others have demonstrated to function at the nexus of pathways controlling proliferation, differentiation and survival of malignant epithelial cells in HNSCC. By developing a physiologic mouse model of HNSCC we demonstrated that these tumors are addicted to high levels of p63, which critically activates a paracrine FGFR signaling axis that is essential for tumor cell survival. The physiologic significance of these observations is further supported by the demonstration that p63/p73 are direct mediators of chemosensitivity in HNSCC which is abrogated by Bcl-2 up-regulation, a mediator of therapeutic resistance. HNSCC exhibits extensive cellular heterogeneity within the neoplastic compartment, and successful therapy must target the regenerative population that maintains the self-renewing capacity of the tumor. Here we describe a novel and powerful transcriptional program mediated by p63 that drives regenerative proliferation in HNSCC. In Aim 1 we will perform in vivo studies to credential a key p63-associated co-factor that is required for the regenerative program, test effects on chromatin, and identify the downstream transcriptional and functional contributions. In Aim 2 we will validate an additional p63-associated co-factor and pharmacologic target which we hypothesize to mediate a central transcriptional program relevant to tumor progression. In Aim 3 we describe molecular analysis of patient samples and in vitro drug screens, leading to our discovery of a new approach to treat platinum-resistant HNSCC that leverages cross-talk between oncogenic and MAP kinase pathways. We will pursue this approach by employing genetic models, clinical pharmacologic inhibitors, and correlative tissue studies with patients enrolled in early-phase clinical trials. In addition to improving our knowledge of the basic biology of HNSCC, these studies will advance the goal of uncovering novel and viable therapeutic targets to improve treatment outcomes in this disease.