P63 Mechanisms and mediators in HNSCC

项目总结 该项目的长期目标是寻找新的、更有效、毒性更小的Head疗法 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的调控。P53蛋白家族在细胞周期中起着关键作用。 HNSCC的发病机制。P53基因本身就是其中大多数突变失活的目标。 无论治疗方式如何，肿瘤和p53突变肿瘤都是高度致命性的。相比之下，相关的 家族成员p63没有突变，但显著过度表达和/或受到基因组扩增的影响 在大多数情况下。P63是一种谱系特异性的正常上皮发育的主要调节因子，我们 而其他的已经证明在控制增殖、分化的通路中起作用。 恶性上皮细胞在HNSCC中的存活情况。通过建立HNSCC生理性小鼠模型 我们证明，这些肿瘤对高水平的p63上瘾，p63关键地激活旁分泌。 FGFR信号轴对肿瘤细胞的生存至关重要。它们的生理学意义 P63/p73是一种直接的调节因子，这进一步支持了我们的观察。 化疗敏感性在HNSCC中被作为治疗耐药的媒介的Bcl2上调而取消。 HNSCC在肿瘤内表现出广泛的细胞异质性，并成功地进行了治疗 必须以保持肿瘤自我更新能力的再生人口为目标。在这里我们 描述一种由p63介导的驱动再生增殖的新颖而强大的转录程序 在HNSCC。在目标1中，我们将进行活体研究，以证明关键的p63相关辅助因素是 再生程序所需的，测试对染色质的影响，并确定下游转录 和功能贡献。在目标2中，我们将验证另一个与p63相关的辅助因子和 我们假设的调节与肿瘤相关的中枢转录程序的药理靶点 进步。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，这种方法利用 致癌和MAP激酶通路。我们将通过使用遗传模型、临床模型来实现这一方法 参与早期临床试验的患者的药理抑制剂和相关组织研究。在……里面 除了提高我们对HNSCC基本生物学的认识外，这些研究还将推进 发现新的和可行的治疗目标，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.