P63 mediators as therapeutic targets in HNSCC

该项目的长期目标是寻找新的、更有效、毒性更低的治疗方法。 了解颈部鳞状细胞癌(HNSCC)及其相关癌症的功能和调控 P53家族成员p63和p73。P53蛋白家族在恶性黑色素瘤的发病机制中起关键作用。 HNSCC。在这些肿瘤中，超过50%的肿瘤中，p53基因本身是突变失活的目标。相比之下， 相关的家族成员p63没有突变，但显著过度表达，并受基因组的影响 大多数病例扩增。P63对HNSCC的贡献进一步得到了基本作用的支持 我们和其他人已经证明了p63在促进增殖、黏附信号和再生方面的作用。 在正常的上皮细胞发育过程中的潜能。在HNSCC细胞中，p63也是一种凋亡抑制因子 由相关家庭成员p73调解。促凋亡p73本身在原发HNSCC中高表达，并且 P63通过与p73的物理结合和直接结合抑制肿瘤细胞的凋亡 P73调控的促凋亡基因中的调控元件。它们的生理学意义 有证据表明，p63/p73是化疗敏感性的直接介体，这支持了我们的观察。 以铂为基础的化疗治疗HNSCC和其他肿瘤。综上所述，这些发现提供了一个强有力的 进一步研究p63/p73的生化调控和功能贡献 HNSCC。这项提案描述了一种系统的方法来揭示p63/p73的调控及其作用。 在体内维持肿瘤的能力。我们假设p63/p73调节因子的一个子集起内源性作用。 HNSCC中的细胞凋亡抑制因子。我们已经完成了全基因组筛查，以确定这样的调控因子， 其中一些可能是HNSCC有吸引力的治疗靶点。在AIM I中，我们将确定以下哪一项 最相关的因素是：1)完成初步候选人的补充功能筛选；2) 对最有吸引力的候选人进行直接验证；iii)将他们的表达与临床相关联 原发肿瘤标本的结果，以及iv)进行生化研究以确定其机制。 基于p63在正常上皮发育中的多效性作用，我们推测p63可能参与了 HNSCC肿瘤的体内维持通过多条途径进行。在AIM II中，我们将通过i)检验这一假设 建立和验证HNSCC动物模型；ii)将该模型与p63条件等位基因杂交，其条件等位基因 切除可以在时间上控制；iii)确定内源性p63体细胞失活对 肿瘤进展，以及iv)确定内源性p63失活的细胞和生化效应 这个HNSCC模型。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靶点的目标，以改善本病的治疗结果 疾病。

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 more than 50% of these tumors. In contrast, the related family member p63 is not mutated but is dramatically overexpressed andlor subject to genomic amplification in the majority of cases. A contribution of p63 to HNSCC is further supported by the essential role we and others have demonstrated for p63 in promoting proliferation, adhesion signaling, and regenerative potential during normal epithelial development. In HNSCC cells p63 also functions as a repressor of apoptosis mediated by the related family member p73. Pro-apoptotic p73 itself is overexpressed in primary HNSCC, and p63 suppresses apoptosis in these tumors through both physical association with p73 and direct binding to regulatory elements within p73-regulated pro-apoptotic genes. The physiologic significance of these observations is supported by the demonstration that p63/p73 are direct mediators of chemosensitivity to platinum-based chemotherapy in HNSCC and other tumors. Taken together, these findings provide a strong rationale for further studies to understand the biochemical regulation and functional contribution of p63/p73 in HNSCC. This proposal describes a systematic approach to uncovering the regulation of p63/p73 and their role in tumor maintenance in vivo. We hypothesize that a subset of p63/p73 regulators function as endogenous apoptosis suppressors in HNSCC. We have completed a genome wide-screen to identify such regulators, some which may represent attractive therapeutic targets in HNSCC. In Aim I we will determine which of these factors are most relevant by i) completing a complementary functional screen of initial candidates; ii) performing direct validation of the most attractive candidates; iii) correlating their expression with clinical outcome in primary tumor specimens, and iv) performing biochemical studies to determine their mechanism. Based on its pleiotropic role in normal epithelial development we hypothesize that p63 may contribute to HNSCC tumor maintenance in vivo through multiple pathways. In Aim II we will test this hypothesis by i) developing and validating an animal model of HNSCC; ii) crossing this model to a p63 conditional allele whose excision can be temporally controlled; iii) determining the effect of endogenous p63 somatic inactivation on tumor progression, and iv) determining the cellular and biochemical effects of endogenous p63 inactivation in this HNSCC model. 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.