Author ORCID Identifier

https://orcid.org/0000-0002-4028-3864

Date of Graduation

12-2017

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Faye M. Johnson, M.D., Ph.D.

Committee Member

Michael A. Davies, M.D., Ph.D.

Committee Member

Gordon B. Mills, M.D., Ph.D.

Committee Member

Mitchell J. Frederick, Ph.D.

Committee Member

Andrew J. Bean, Ph.D.

Abstract

Head and neck squamous cell carcinoma (HNSCC) affects various mucosal sites of the upper aerodigestive tract, including the nasal and oral cavities, the nasopharynx, and the oropharynx. More than five hundred thousand new cases of HNSCC occurred in 2011 alone, with 50,000 reported cases in the United States. This trend made HNSCC the seventh most common non-skin cancer worldwide (Ferlay et al., 2015). Although significant epidemiological and pathological advancements have been made, survival rates have not improved much over the last 40 years, leaving a mortality rate that remains at approximately 50%. An unbiased drug screen demonstrated that HNSCC cell lines bearing NOTCH1 inactivating mutations are sensitive to PI3K and dual PI3K/mTOR inhibitors, leading us to investigate the interaction of these pathways in HNSCC. The NOTCH pathway plays key roles in cell proliferation, differentiation, and apoptosis. With inactivating mutations in 18% of 510 HNSCC patient samples, NOTCH1 is one of the most frequently altered genes in HNSCC (TCGA, Provisional). In 21 patients with HNSCC tumors, approximately 28 NOTCH1 mutations predicted tumor suppressive properties (Agrawal et al., 2011). The PI3K/mTOR pathway is a critical regulator of cell growth, proliferation, differentiation, and survival. It is the most frequently altered pathway in HNSCC, occurring in approximately 80% of HNSCC tumors (Iglesias-Bartolome R, et al., 2013). Previous research suggests that NOTCH1 regulates PI3K-AKT and mTOR1 signaling in T-ALL cells by decreasing PTEN expression. In addition, blocking NOTCH1 activity has been shown to upregulate PTEN activity in T-ALL cells via Hes1 downregulation (Palomero T, et al., 2007). Unfortunately, the mechanism of communication between the two pathways is unknown in HNSCC. Understanding the interaction between the NOTCH1 and PI3K/AKT/mTOR signaling pathways presents them as essential targeting agents that may have a significant impact on modern therapeutic medicine. In this research, we sought to investigate whether the NOTCH1 pathway regulates the activity of the PI3K-PTEN-AKT/mTOR pathway in HNSCC in vitro. The data of various experiments aimed at manipulating NOTCH1 activation and HES1 expression suggests that the NOTCH1 pathway does not affect the PI3K-PTEN-AKT/mTOR pathway in HNSCC.

Keywords

NOTCH, PI3K, mTOR, HES1, PTEN, Head and Neck Squamous Cell Carcinoma, Interaction, Crosstalk, Targeted Therapies, Signaling Pathway

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