Head and neck squamous cell carcinomas (HNSCC) are frequently lethal and predictive biomarkers to guide treatment are lacking. We recently determined the mutational profile of 74 HNSCC, and mutations of genes in the PI3K signaling pathway were detected in nearly one quarter of these cancers. These results were subsequently validated in larger HNSCC cohorts including the HNSCC TCGA. As the PI3K pathway is eminently targeted with multiple drugs that are in early phase clinical development, this provides an immediate opportunity to define predictive biomarkers and implement potentially effective therapeutic approaches for HNSCC. We have developed novel HPV-positive and HPV-negative HNSCC models to identify oncogenic """"""""driver"""""""" mutations in this cancer. In addition, we can assess PI3K pathway mutation and amplification in human HNSCC tumors to be grown as heterotopic tumorgrafts in mice as well as tumors from HNSCC patients enrolled on a novel phase II trial of a PI3K pathway inhibitor. This project will therefore elucidate the role of PI3K activation as a biomarker in HNSCC progression, and facilitate the identification of a subset of HNSCC patients where treatment with a PI3K targeting agent represents an effective therapeutic strategy.
Head and neck squamous cell carcinomas (HNSCC) account for the majority of tumors that arise in the mucosal of the head and neck. EGFR is the only FDA-approved molecular therapeutic target, yet the critical therapeutic biomarker(s) for HNSCC remains unknown. We recently determined the mutational profile of 74 HNSCC, and PI3K pathway mutations were detected in over one third of these cancers. Further investigation demonstrated that amplification of genes in the PI3K pathway is also found in about 25% of HNSCC, suggesting that PI3K pathway activation represents a biomarker of HNSCC. We have developed novel HPV- positive and HPV-negative HNSCC models to identify oncogenic driver mutations. The proposed studies will: 1) determine the contribution of individual PI3K pathway mutations and/or amplification to HNSCC growth;2) elucidate the biological impact of small molecule inhibitors targeting specific components in the PI3K pathway, either alone or in combination with EGFR inhibitors, in HNSCC models, engineered to mimic the diversity of PI3K pathway aberrations found in human tumors;and 3) determine whether PI3K pathway mutations and/or gene amplification serve as predictive biomarkers in mediating the in vivo antitumor effects of PI3K and EGFR targeting strategies in preclinical HNSCC models and HNSCC patients enrolled in a phase II trial of BKM120 in combination with cetuximab.
|Brand, Toni M; Hartmann, Stefan; Bhola, Neil E et al. (2018) Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer. Cancer Res 78:2383-2395|
|Johnson, Daniel E; O'Keefe, Rachel A; Grandis, Jennifer R (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15:234-248|
|Kemmer, J D; Johnson, D E; Grandis, J R (2018) Leveraging Genomics for Head and Neck Cancer Treatment. J Dent Res 97:603-613|
|Santuray, Rodell T; Johnson, Daniel E; Grandis, Jennifer R (2018) New Therapies in Head and Neck Cancer. Trends Cancer 4:385-396|
|Frazier, Nicole Michael; Brand, Toni; Gordan, John D et al. (2018) Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation. Oncogene :|
|Cho, Janice; Johnson, Daniel E; Grandis, Jennifer R (2018) Therapeutic Implications of the Genetic Landscape of Head and Neck Cancer. Semin Radiat Oncol 28:2-11|
|Lee, Yoon Se; Johnson, Daniel E; Grandis, Jennifer R (2018) An update: emerging drugs to treat squamous cell carcinomas of the head and neck. Expert Opin Emerg Drugs :1-17|
|Algazi, Alain P; Grandis, Jennifer R (2017) Head and neck cancer in 2016: A watershed year for improvements in treatment? Nat Rev Clin Oncol 14:76-78|
|Brand, Toni M; Hartmann, Stefan; Bhola, Neil E et al. (2017) Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients. Clin Cancer Res 23:3072-3083|
|Xu, Mary Jue; Johnson, Daniel E; Grandis, Jennifer R (2017) EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev 36:463-473|
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