Author

Heng-Wei Hsu

Abstract

Tumor angiogenesis is a hallmark of advanced cancers and promotes invasion and metastasis. Over 90% of head and neck squamous cell carcinomas (HNSCC) express angiogenic factors such as vascular endothelial growth factor (VEGF). Since radiotherapy is one of the most commonly used treatments for HNSCC, it is imperative to identify the interactions between antiangiogenic therapy and radiotherapy, and to develop combination therapy to improve clinical outcome. The mechanisms between antiangiogenic agents and ionizing radiation are complicated and involve many interactions between the vasculature, tumor stroma and tumor cells. The proliferation and metastasis of tumor cells rely on angiogenesis/blood vessel formation. Rapid growing tumors will cause hypoxia, which up-regulates tumor cell survival factors, such as VEGF and hypoxia-inducing factor-1α (HIF-1α), giving rise to more tumor proliferation, angiogenesis and increased radioresistance. Thus, agents that target new tumor vessel formation can modulate the tumor microenvironment to improve tumor blood flow and oxygenation, leading to enhanced radiosensitivity. Signal transducer and activator of transcription 3 (STAT3), is a potential modulator of VEGF expression and regulates cell-cycle progression, angiogenesis, metastasis and apoptosis. Approximately 80% of HNSCC exhibit up-regulation of STAT3 expression, which theoretically mediates radio-resistance and chemo-resistance. Therefore, inhibition of STAT3 may render tumor cells growth arrest and/or apoptosis. Recently it has been discovered that DNA damage can induce the expression and secretion of interleukin-6 (IL-6), resulting in the activation of STAT3 signaling pathway. Therefore, by inhibiting STAT3, one can also inhibit DNA damage repair and induce apoptosis in tumor cells. In this project, we tested the feasibility of Linifanib (ABT-869), a multi-receptor tyrosine kinase inhibitor of VEGF and platelet derived growth factor (PDGF) receptor families, on radio-sensitization of HNSCC. The results show that Linifanib (ABT-869) can induce an antitumor effect and radio-sensitize HNSCC cells via inhibition of STAT3 signaling pathway. Combining antiangiogenic targeted agent such as Linifanib (ABT-869) with radiation to enhance tumor killing and apoptosis may provide a novel therapeutic strategy and improve efficacy of radiation against HNSCC in the future.

LLU Discipline

Pharmacology

Department

Basic Sciences

School

School of Medicine

First Advisor

Mirshahidi, Saied

Second Advisor

Chen, Chien-shing

Third Advisor

Gridley, Daila S.

Fourth Advisor

Wall, Nathan R.

Fifth Advisor

Zhang, Lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2013

Date (Title Page)

12-2013

Language

English

Library of Congress/MESH Subject Headings

Head and Neck Neoplasms - Pathology; Carcinoma - Squamous Cell; Cell Line - Tumor; Cell Proliferation; Cell Survival - Radiation Effects; Apoptosis Inducing Factor; Focal Adhesion Protein-Tyrosine Kinases - Metabolism; Protein Kinase Inhibitors; Indazoles - Therapeutic Use; Phenylurea Componds - Therapeutic Use; Radiation-Sensitizing Agents - Therapeutic Use; Chemoradiotherapy; Radiation Tolerance

Subject - Local

Tumor Angiogenesis; Vascular Endothelial Growth Factor; Antiangiogenic Therapy; Tumor Microenvironment; Signal Transducer and Activator of Transcription 3 (STAT3)

Type

Dissertation

Page Count

85

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives