Date of Award

January 2018

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Wendell G. Yarbrough

Abstract

Patients with head and neck cancer suffer not solely from disease but also from sequelae of radiation and chemotherapy treatment, and there is a large, unmet need to both develop novel therapies and improve existing ones to decrease deleterious, life-long side effects and improve patient survival. In the last several years, growing evidence has suggested that head and neck cancer represents two distinct disease entities based on Human Papilloma Virus (HPV) status. Unfortunately, HPV status is currently only used for prognosis and not for guiding management. Subsequently, this work focuses on 1) developing a novel targeted therapy for HPV-positive (HPV(+)) head and neck cancers and 2) improving the efficacy of current treatments for HPV- negative (HPV(-)) head and neck cancers. In the first part of this study, using HPV(+) and HPV(-) head and neck cancer cell lines, we show that roscovitine, a cyclin-dependent kinase (CDK) inhibitor that inhibits CDK-1, CDK-2, CDK-5, CDK-7, and CDK-9 due to competitive binding at the kinase ATP site causes significant DNA damage followed by p53-dependent cell death in HPV(+), but not in HPV(-), head and neck cancer cells. We also show that low dose roscovitine administration significantly inhibits the growth of HPV(+) xenografted tumors in mice without causing any detectable side effects, further reinforcing the potential of roscovitine as a targeted therapy for HPV(+) HNSCC. In the second part of the study, we use a number of different cancer cell lines with variable p53 status (either wild-type, mutant, or null p53), along with embryonic fibroblasts derived from genetically engineered mice, to show that knockdown of leucine zipper-containing ARF-binding protein (LZAP) eliminates the p53 protein independently of its mutation status, subsequently protecting wild-type p53 cells (i.e., healthy tissue) from DNA damage-induced cell death (e.g. such as that caused by radiation), while rendering cells expressing mutant p53 (i.e., HPV(-) HNSCCs) more sensitive to the treatment. Our study highlights the need to develop different therapeutic strategies for HPV(+) and HPV(-) HNSCC patients, specifically taking into account their individual genetic defects and “Achilles’ heels.”

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This is an Open Access Thesis.

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