Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pathology

First Advisor

Andrean L. Simons-Burnett

Abstract

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) is a major obstacle in the success of head and neck cancer therapy. Despite efforts by several groups to understand the mechanisms of resistance to tyrosine kinase inhibitors such as erlotinib, there has been little success in improving the patient survival. Given that there are a number of ongoing clinical trials testing the efficacy of erlotinib in head and neck cancer, it is essential to investigate the novel mechanisms of erlotinib resistance to improve its efficacy and patient survival. This dissertation addresses this issue of erlotinib resistance in head and neck cancer, underscoring the role of inflammatory cytokine signaling. Chapter 1 introduces the problem of erlotinib resistance and discusses the potential link between inflammatory signaling and cancer progression and erlotinib resistance in head and neck squamous cell carcinoma. Chapter 2 discusses the role of the cytokine interleukin-6 signaling in acquired resistance to erlotinib in head and neck squamous cell carcinoma. Chapter 3 describes the role of IL-1 signaling in acquired resistance to erlotinib in head and neck squamous cell carcinoma. Chapter 4 discusses the specific role of IL-1α (an agonistic ligand for IL-1 signaling) in acquired resistance to erlotinib in head and neck squamous cell carcinoma. Chapter 5 discusses ideas to test for future work in this field. Altogether, this dissertation endeavors to emphasize the contributory role of inflammatory cytokine signaling in erlotinib resistance in head and neck squamous cell carcinoma so that it helps in the development of effective anti-cancer therapies and biomarkers of resistance and/or response in HNSCC.

Public Abstract

The majority (up to 90%) of head and neck cancers (HNCs) have increased levels and activity of a molecule called ‘epidermal growth factor receptor’ (EGFR). Based on this, drugs that inhibit EGFR have been development. Erlotinib (Tarceva®) is an EGFR-inhibitor to which, surprisingly, only a small subset (~5%) of head and neck cancer patients showed response. However, the majority of respondents develop resistance to erlotinib relatively quickly. Therefore, in order to improve the efficacy of erlotinib, it is essential to understand the mechanisms of erlotinib resistance in HNC patients. This thesis work addresses the issue of erlotinib resistance in HNC. Inflammation is known to play a critical role in the progression of various cancers including HNC. Chapter 1 introduces the problem of erlotinib resistance and discusses the potential link between inflammation, cancer progression and erlotinib resistance in HNC. Chapter 2 discusses the role of an inflammatory molecule called interleukin-6 (IL-6) in acquired resistance to erlotinib in HNC. Chapter 3 describes the signaling role of another inflammatory molecule called interleukin-1 (IL-1; fever molecule) in acquired resistance to erlotinib in HNC. Chapter 4 discusses the specific role of an inflammatory molecule called interleukin-1 alpha (IL-1M), which triggers IL-1 signaling in acquired resistance to erlotinib in HNC. Chapter 5 discusses ideas to test for future work in this field. Overall, this thesis work uncovers the contributory role of inflammation (or inflammatory molecules) in resistance to erlotinib in HNC. We hope these results would propel the development of effective anti-cancer therapies in HNC patients.

Keywords

publicabstract

Pages

xii, 115

Bibliography

100-103

Copyright

Copyright 2016 Aditya Stanam

Included in

Pathology Commons

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