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.
Head and Neck Squamous Cell Carcinoma (HNSCC) is a common form of human cancer for which little progress has been made in long-term treatment outcomes over the last 30 years. This project aims ultimately to improve treatment success in HNSCC and related tumors, by identifying molecular pathways that function as the tumor cell's Achilles'heel. Once identified, these tumor vulnerabilities can be exploited through the development of new targeted therapies.
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