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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE023685-03
Application #
9040931
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Venkatachalam, Sundaresan
Project Start
2014-05-01
Project End
2019-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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

Showing the most recent 10 out of 37 publications