Author(s)
Theresa W. Guo, MD
Daria A. Gaykalova, PhD
Joseph A. Califano, MD
Affiliation(s)
Johns Hopkins Hospital
Abstract:
Educational Objective: At the conclusion of this presentation, the participants should be able to discuss the potential role of NOTCH family of receptors in head and neck cancer. Objectives: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide, with approximately 60,000 new diagnoses in the United States annually. In recent genomic analyses, NOTCH1 mutations were identified in 10-15% of HNSCC tumors, and evidence of activation of the NOTCH pathway has also been shown. Study Design: Based on these findings, we sought to study the role of other NOTCH family member receptors in these cancers, and therefore we performed genomic analysis and functional studies to elucidate their potential role in the carcinogenesis of HNSCC. Methods: Gene expression analysis was performed using TCGA RNA seq data. Tumors with any mutations in NOTCH family receptors were excluded. For functional in vitro assays, siRNA were obtained for NOTCH1, NOTCH2, and NOTCH3. Transient knockdown was achieved through transfection using lipofectamine delivery. Cell growth was assessed over 72 hours following transfection using alamarBlue reagent. Invasion assays were performed over 24-48 hours using matrigel reagent in multiple cell lines. Results: We interrogated the TCGA RNA seq data for gene expression analysis and found that after excluding tumors with NOTCH mutations, expression of NOTCH1 and NOTCH3 were both significantly associated with NOTCH pathway activation and high HEY expression. Functional in vitro assays showed that silencing of multiple NOTCH family receptors inhibited of cell proliferation and invasion in functional in vitro assays, in both HPV positive and HPV negative HNSCC cell lines. Conclusions: These results point to the potential role of NOTCH inhibitors, some of which are in phase I clinical trials, as a targeted therapy for HNSCC.