Head and neck squamous cell carcinoma (HNSCC) is a morbid and lethal malignancy where increased understanding of the genetic alterations that characterize this cancer has yet to identify predictive biomarkers to guide therapy.PIK3CA is the most commonly altered oncogene in both human papillomavirus (HPV)- negative (34% of cases) and HPV-positive (56% of cases) HNSCC. In the current funding period we found that PIK3CA mutation or amplification is a biomarker of poor prognosis in HNSCC and that only a subset of PIK3CA- mutated HNSCC tumors are sensitive to PI3K pathway inhibition. Further investigation suggested that HPV oncoproteins regulate the antitumor effects of PI3K inhibitors. We hypothesize that elucidation of the biologic impact of individual PIK3CA alterations and mechanisms of PI3K inhibitor resistance will guide therapeutic strategies to improve clinical outcomes for HNSCC patients whose tumors contain genetic alterations that activate PI3K signaling. To test this hypothesis we propose three Specific Aims.
Specific Aim 1 will elucidate the protein interactome and synthetic lethal dependencies for each mutant p110? demonstrated to ?drive? HNSCC survival using: a) affinity purification- mass spectrometry (AP-MS) in HPV+ and HPV- HNSCC models; and b) genetic interaction CRISPR screening.
In Aim 2 we will determine the impact of targeting PI3K alone and in combination with inhibition of individual mutant p110??interacting proteins in both immunocompetent and immunodeficient HNSCC preclinical models.
Aim 3 will examine biomarkers of PI3K inhibitor resistance by analyzing paired biospecimens and PDXs developed from HNSCC patients enrolled on a window-of-opportunity trial of the p110? PI3K inhibitor BYL719. Successful completion of these studies has the potential to change clinical practice in HNSCC by providing effective treatment strategies for patients based on the specific PIK3CA mutational status of their tumor.

Public Health Relevance

Head and neck squamous cell carcinoma (HNSCC) is characterized by frequent mutation of the PIK3CA oncogene, and we have shown that both canonical and selected noncanonical PIK3CA mutations ?drive? HNSCC growth. The proposed studies will identify key therapeutic targets present in the protein interactomes of HNSCC cells and tumors expressing PIK3CA genetic alterations. Additionally, the impact of PI3K targeting strategies on both cancer cells and immune cells will be explored in HNSCC preclinical models and in biospecimens from HNSCC patients enrolled on a window-of-opportunity trial of a p110? PI3K inhibitor.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Wang, Chiayeng
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University of California San Francisco
Schools of Medicine
San Francisco
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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
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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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