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 ?- 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 ?-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.
We propose to define molecular links between ?-catenin/CBP activity and aggressive cells in oral pre- cancerous lesions, and to identify therapeutic interventions in head and neck cancer. We postulate that inhibition of ?-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.
