Intercepting head and neck cancer using functional genomics approaches

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PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is a devastating malignancy associated with high morbidity, poor survival rates, and limited treatment options; the majority of cases presenting as oral cavity tumors, or oral squamous cell carcinoma (OSCC). Cell fate determination and CSC maintenance and expansion are controlled by Wnt/-catenin signaling, shown to underlie HNSCC pathobiology however, the cellular, genomic and epigenetic details of Wnt/-catenin deregulation in HNSCC remain undefined. In our recent studies, we found inhibition of -catenin/CBP signaling – via pharmacological grade small molecule inhibitors, ICG-001 and E7386 – interferes with OSCC tumor growth and metastasis and elevated β- catenin/CBP signaling in primary OSCC tumors is associated with tumor progression and poor patient survival. Building on these preliminary findings, our project includes a total of three aims. Aim 1 seeks to define the role of -catenin/CBP in HNSCC initiation and progression to advanced disease using the murine 4NQO oral carcinogenesis model. In Aim 2 we will validate transcriptional signatures associated with -catenin/CBP in pre-cancerous human tissues and integrate this data with publicly available multi-omics datasets. Lastly, Aim 3 plans to reconstruct gene regulatory networks using high-dimensional Bayesian inference to use in modeling potential targets for intervention strategies and combinatorial therapies. Overall, our project aims to define molecular links between -catenin/CBP activity and aggressive cells in pre-cancerous lesions, and to identify therapeutic interventions in head and neck cancer. We postulate that inhibition of β-catenin/CBP activity will intercept early disease and interfere with its progression, and that the E7386 inhibition signature will have prognostic value for OSCC diagnosis and treatment.