Gyanchandani, Rekha
(2013)
MOLECULAR DETERMINANTS OF RESPONSE
TO ANTIANGIOGENIC THERAPIES IN
PRECLINICAL MODELS OF HEAD AND NECK
SQUAMOUS CELL CARCINOMA.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Abstract
Background
Head and neck squamous cell carcinoma (HNSCC) is the eighth leading cancer by incidence worldwide. In the past 5 decades there have been significant advances in surgery and chemoradiotherapy, but very little improvement in survival rates. Hence, there is a pressing need to develop new therapeutic strategies in HNSCC. Antiangiogenic therapy represents a promising strategy in at least a subset of patients. Currently, there are no reliable predictive and resistance biomarkers to identify those patients most likely to benefit. Studies using relevant preclinical models that identify mechanisms of resistance to antiangiogenic agents will help meet these challenges.
Principal Findings
In this dissertation, we established preclinical models of intrinsic and acquired resistance to anti-VEGF antibody bevacizumab and identified potential biomarkers of drug response.
To characterize mechanisms of intrinsic resistance, we evaluated the angiogenic profile of HNSCC cells from bevacizumab-sensitive and -resistant tumor models using antibody array. We showed that resistant cells expressed higher levels of proangiogenic factors including interleukin-8 (IL-8). We identified PI3K and IL-1α signaling as the molecular basis for overexpression of IL-8. Downregulation of IL-8 resulted in sensitization of resistant tumors to bevacizumab. Overexpression of IL-8 in sensitive tumors conferred resistance to bevacizumab. Serum analysis of HNSCC patients treated with a bevacizumab-containing regime indicated high baseline IL-8 levels in a subset of patients refractory to treatment but not in responders.
In a novel xenograft model of acquired resistance, human-specific microarray analysis revealed upregulation of angiogenesis-related genes including fibroblast growth factor-2 (FGF2), fibroblast growth factor receptor-3 (FGFR3), phospholipase C gamma-2 (PLCg2), frizzled receptor-4 (FZD4), chemokine [C-X3-C motif] ligand-1 (CX3CL1), and chemokine [C-C motif] ligand-5 (CCL5). Upstream genes PLCg2, FZD4, CX3CL1, and CCL5 regulated increased expression of FGF2 via increased extracellular signal-regulated kinase (ERK) signaling. Co-targeting VEGF and FGFR sensitized resistant tumors to bevacizumab.
Conclusions and Significance
Our work has identified two distinct molecular mechanisms of resistance to bevacizumab in preclinical HNSCC models. IL-8 signaling mediated intrinsic resistance while upregulation of FGF signaling in response to anti-VEGF therapy contributed to acquired resistance. Above findings provide a mechanistic rationale for co-targeting these pathways in future clinical trials to enhance the therapeutic efficacy of antiangiogenic therapy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Gyanchandani, Rekha | reg31@pitt.edu | REG31 | |
|
| ETD Committee: |
|
| Date: |
30 April 2013 |
| Date Type: |
Publication |
| Defense Date: |
12 April 2013 |
| Approval Date: |
30 April 2013 |
| Submission Date: |
30 April 2013 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
113 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Pharmacology and Chemical Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Angiogenesis, Acquired resistance, Bevacizumab, Biomarker, FGF, HNSCC,
Intrinsic resistance, IL-8. |
| Date Deposited: |
30 Apr 2013 12:53 |
| Last Modified: |
19 Dec 2016 14:40 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/17327 |
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