All ETDs from UAB

Advisory Committee Chair

Eddy S Yang

Advisory Committee Members

John M Parant

Eben L Rosenthal

David G Standaert

Robert C Van Waardenburg

Kurt R Zinn

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with high rates of recurrence and mortality. Unlike other cancer types, genome sequencing studies have failed to produce clinically actionable targets to improve HNSCC management. Therefore, alternative methods are needed to study the molecular mechanisms responsible for disease progression and response to therapy. The focus of this research was to determine how dysregulation of cell signaling pathways affects outcomes in HNSCC. In HPV-positive HNSCCs, we hypothesized that HPV induces dysregulation of the DNA damage response which mediates differences in therapeutic sensitivity and survival. We identified a defect in DNA double strand break repair affecting both homologous recombination and non-homologous end joining. Although HPV-positive cells were able to sense and respond to DNA damage, expression and recruitment of downstream repair proteins BRCA2 and DNA-PkCS was deficient. This defect correlated with in-creased sensitivity to PARP inhibitors in cell line and patient-derived xenografts. We then formed a second hypothesis that expression of DNA-PkCS is variable in the HPV-positive subtype which contributes to inconsistency in disease progression. Differential DNA-PkCS expression was confirmed in clinical samples. Interestingly, protein levels were inversely related to the abundance of HPV E6/E7 mRNA and trended towards significance as a predictor of disease recurrence. Lastly, in vitro knockdown of DNA-PkCS resulted in increased therapeutic sensitivity and decreased invasion in HNSCC cell lines. In HPV-negative HNSCCs, we hypothesized that activation of Notch signaling alters cell processes contributing to poor patient outcomes. We identified an association between activation of the Notch pathway and mortality in two independent data sets. High Notch activity correlated with increased expression of the pro-invasive gene FGF1. Notch activation also prompted an increase in cell migration and invasion which was dependent on FGF1 expression. Cell proliferation, cell cycle profile, and sensitivity to radiation were unaffected by Notch activity. These results indicate that DNA repair and Notch signaling are dysregulated in HNSCC, leading to variability in characteristics such as therapeutic sensitivity and tumor progression. Importantly, we determined that DNA-PkCS and FGF1 are markers of signaling activity which should be studied further as potential therapeutic targets in this disease.

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