Tissue-Specific Vascular Endothelial Signals and Vector Targeting, Part A (eBook)

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2009 | 1. Auflage
140 Seiten
Elsevier Science (Verlag)
978-0-08-096246-7 (ISBN)

The field of genetics is rapidly evolving and new medical breakthroughs are occuring as a result of advances in knowledge of genetics. This series continually publishes imporatnt reviews of the broadest interest to geneticists and their colleagues in affiliated disciplines.

* Provides contrasting roles of VEGF, giving ,researchers a better understanding of the underlying mechanisms of VEGF
*Includes ,chapters that review research employing a variety of organisms, allowing researchers to compare and contrast
*Focuses on ,material that translates basic research to real-life treatment applications, showing primary researchers how the basic science is being used in the clinical setting

The field of genetics is rapidly evolving, and new medical breakthroughs are occurring as a result of advances in our knowledge of genetics. This series continually publishes important reviews of the broadest interest to geneticists and their colleagues in affiliated disciplines.This thematic volume reviews the latest research findings in the area of vascular proteomics related to the receptors of the vascular endothelium, and expands insights into diseases that exhibit distinct vascular characteristics, including cancer, obesity, and inflammation. Provides contrasting roles of VEGF, giving researchers a better understanding of the underlying mechanisms of VEGF Includes chapters that review research employing a variety of organisms, allowing researchers to compare and contrast Focuses on material that translates basic research to real-life treatment applications, showing primary researchers how the basic science is being used in the clinical setting

Front Cover
1
Advances in Genetics
4
Copyright
5
Contents
6
Contributors
8
Chapter 1: Inhibition of Vascular Endothelial Growth Factor Receptor Signaling in Angiogenic Tumor Vasculature
10
I. Introduction
11
II. VEGF/VEGFR Signaling Pathway as a Target of Antiangiogenic Therapy
12
III. Strategies to Inhibit the VEGF/VEGFR Signaling
13
IV. Using VEGFR-2 for Targeted Delivery of Powerful Toxic Agents
17
V. Summary
31
References 31
Chapter 2: Adeno-Associated Viral Vectors and Their Redirection to Cell-Type Specific Receptors
38
I. Introduction
39
II. Capsid Modifications of AAV to Target Cellular Receptors
47
III. Selecting Novel AAV Vectors from Combinatorial Libraries
50
IV. Perspectives
59
References 60
Chapter 3: Tissue-Specific Targeting Based on Markers Expressed Outside Endothelial Cells
70
I. Introduction
71
II. Nonendothelial Tissue-Specific Targets of Systemically Administered Agents
78
III. Concluding Remarks and Future Directions
99
Acknowledgment
101
References 101
Chapter 4: Ligand-directed Cancer Gene Therapy to Angiogenic Vasculature
112
I. Introduction
113
II. Therapeutic Concepts in Cancer Gene Therapy
114
III. Vectors for Ligand-directed Gene Delivery
118
IV. Ligands for Targeting Angiogenic Vasculature
121
V. Conclusion
124
References 124
Index
132
Color Plates
136

Inhibition of Vascular Endothelial Growth Factor Receptor Signaling in Angiogenic Tumor Vasculature

Marina V. Backer, Carl V. Hamby† and Joseph M. Backer

*SibTech, Inc., Brookfield, Connecticut 06804, USA

†Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, USA

Abstract

Neovascularization takes place in a large number of pathologies, including cancer. Significant effort has been invested in the development of agents that can inhibit this process, and an increasing number of such agents, known as antiangiogenic drugs, are entering clinical trials or being approved for clinical use. The key players involved in the development and maintenance of tumor neovasculature are vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), and therefore VEGF/VEGFR signaling pathways have been a focus of anticancer therapies for several decades. This review focuses on two main approaches designed to selectively target VEGFRs, inhibiting VEGFR with small molecule inhibitors of receptor tyrosine kinase activity and inhibiting the binding of VEGF to VEGFRs with specific antibodies or soluble decoy VEGF receptors. The major problem with these strategies is that they appeared to be effective only in relatively small and unpredictable subsets of patients. An alternative approach would be to subvert VEGFR for intracellular delivery of cytotoxic molecules. We describe here one such molecule, SLT–VEGF, a fusion protein containing VEGF121 and the highly cytotoxic catalytic subunit of Shiga-like toxin.

I. Introduction

Growth of primary tumor and metastatic lesions beyond a few millimeters requires neovascularization that combines angiogenesis and vasculogenesis. In angiogenesis, endothelial cells of existing blood vessels undergo a complex process of reshaping, migration, growth, and organization into new vessels (Folkman, 1995). In vasculogenesis, endothelial progenitor cells migrate from the bone marrow to sites of angiogenesis and contribute significantly to the growth of new blood vessels (Rafii et al., 2002). Under normal circumstances, neovascularization, widely known under the name “angiogenesis,” occurs during embryonic development, wound healing, and development of the corpus luteum. However, neovascularization takes place in a large number of pathologies, such as solid tumor growth, various eye diseases, chronic inflammatory states, and ischemic injuries. Therefore, significant research effort has been invested in the development of agents that can inhibit neovascularization, commonly known as antiangiogenic inhibitors (reviewed in Bergers and Hanahan, 2008, Gourley and Williamson, 2000, Jubb et al., 2006, Manley et al., 2004, Sledge and Miller, 2002 and Thorpe et al., 2003). The first blockbuster drugs targeting VEGFR have already been approved by Food and Drug Administration (FDA) for treatment of several cancers with ~275,000 new US cases per year (Bergers and Hanahan, 2008, Chu, 2009, Izzedine et al., 2009, Jubb et al., 2006 and Ruan et al., 2009 Mar). The potential of these drugs is enormous, as judged by over 230 US-registered Phase III clinical trials for all major cancers with an estimated 12 million new cases annually, worldwide (Hayden, 2009). This review will focus on strategies designed to selectively target the key players involved in the development and maintenance of tumor neovasculature: vascular endothelial growth factor (VEGF) and its receptors (VEGFRs).

II. VEGF/VEGFR Signaling Pathway as a Target of Antiangiogenic Therapy

A. VEGF is a critical positive regulator of angiogenesis

Several positive and negative regulators control the process of angiogenesis. It is hypothesized that the shift in equilibrium between these regulators, known as the “angiogenic switch,” is responsible for angiogenesis in pathological situations (Hanahan and Folkman, 1996). The crucial positive regulator of angiogenesis is VEGF-A, also known as vascular permeability factor (Ferrara, 2009). VEGF-A is a secreted dimeric glycoprotein produced by many cells. VEGF is a potent angiogenic factor in vivo and induces numerous responses in endothelial cells in tissue culture. There are at least three more members of VEGF family: VEGF-B, -C, and -D (Ferrara, 2009 and Lohela et al., 2009). VEGF-B has a very limited angiogenic potential, and is involved in regulating lipid metabolism in the heart. VEGF-C and VEGF-D induce lymphangiogenesis and have been implicated in stimulating metastasis.

Four different forms of human VEGF (VEGF-A), containing 121, 165, 189, and 206 amino acid residues, arise from alternative splicing of mRNA. The first three forms are common in adult organisms while VEGF206 is expressed during embryonic development. VEGF121 is a circulating form of the growth factor. VEGF165, VEGF189, and VEGF206 contain heparin-binding domain(s) in the C-terminal portion. Interactions with heparin-containing extracellular proteoglycans lead to the deposition of VEGF165 and particularly VEGF189 and VEGF206 in the extracellular matrix. VEGF is expressed by normal and tumor cells and the control of VEGF expression appears to be regulated on several levels (Claffey and Robinson, 1996). Expression of VEGF is upregulated in response to hypoxia and nutritional deprivation, suggesting a feedback loop between tumor growth and the ability of tumor cells to induce host angiogenic responses (Veikkola and Alitalo, 1999).

B. VEGF receptors

VEGFs and their endothelial tyrosine kinase receptors are central regulators of vasculogenesis, angiogenesis, and lymphangiogenesis (Lohela et al., 2009). VEGF signaling through VEGFR-2 is the key process in angiogenesis, and inhibition of VEGF/VEGFR-2 signaling is the core of antiangiogenic strategy for cancer therapy. VEGFR-1 acts mostly as a negative regulator of VEGF-mediated angiogenesis during development, and as a stimulator of pathological angiogenesis when activated by its specific ligands PlGF (placenta-derived growth factor) and VEGF-B. VEGFR-3 is a key player in lymphangiogenesis, and contributes to control of angiogenic sprouting angiogenesis, acting together with VEGF/VEGFR-2.

VEGFR-2 receptor is a single?span transmembrane protein tyrosine kinase expressed predominantly in endothelial cells. VEGFR-2 belongs to the immunoglobulin superfamily. It contains seven Ig-like loops in the extracellular domain and shares homology with the receptor for platelet-derived growth factor (Terman and Dougher-Vermazen, 1996 and Veikkola et al., 2000). VEGF binding to VEGFR-2 induces receptor dimerization followed by tyrosine phosphorylation of the SH2 and SH3 domains in the dimer. Tyrosine phosphorylation activates signal transduction pathways, which leads to calcium mobilization, activation of phospholipases C and D, polymerization of actin, changes in cell shape and chemotactic and mitogenic responses. VEGFR-2/VEGF complex is internalized via receptor-mediated endocytosis (Bikfalvi et al., 1991).

Immunohistochemical analysis indicated that endothelial cells at the sites of angiogenesis express significantly higher numbers of VEGFR-2 than quiescent endothelial cells (Brown et al., 1995, Couffinhal et al., 1997 and Koukourakis et al., 2000). Recent data on molecular imaging of VEGFR in tumors support these observations (Backer et al., 2005, Backer et al., 2007, Blankenberg et al., 2004, Cai et al., 2006, Hsu et al., 2007, Levashova et al., 2008, Wang et al., 2007 and Wang et al., 2009). This difference in VEGFR prevalence presents new opportunities for selective targeting of endothelial cells at the sites of angiogenesis.

The fundamental problem in development of antiangiogenic therapeutics is finding targets that can differentiate between the relatively small number of tumor endothelial cells and the very large (~1012) number of normal endothelial cells in the body; and the VEGF/VEGFR signaling pathway appears to be such a target. A significant number of experimental therapeutics targeting VEGF/VEGFR signaling in tumor vasculature have been tested for all major cancers, and multiple late stage clinical trials for some of these drugs are in progress (Bergers and Hanahan, 2008, Chu, 2009, Izzedine et al., 2009, Jubb et al., 2006 and Ruan et al., 2009 Mar).

III. Strategies to Inhibit the VEGF/VEGFR Signaling

A. Blocking VEGF/VEGFR binding

VEGF- and VEGFR-specific neutralizing antibodies or soluble VEGFR-based traps that prevent binding of VEGF to its receptors present the first antiangiogenic strategy. This strategy is based on the assumption that continuous depravation of VEGF/VEGFR signaling is more detrimental for tumor endothelial cells than it is for normal endothelial cells. The most effective VEGF-specific neutralizing antibody developed so far, bevacizumab (Roche/Genentech, trade name Avastin), is the first FDA-approved drug targeting VEGF/VEGFR signaling pathway. Bevacizumab is a humanized murine monoclonal antibody that binds human VEGF and, therefore, diminishes VEGFR signaling, which is presumably more important for growth and maintenance of tumor endothelium than for normal endothelium. It is approved for treatment of metastatic colorectal cancer in combination with...

Erscheint lt. Verlag	12.11.2009
Sprache	englisch
Themenwelt	Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie
	Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik
	Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
	Technik
ISBN-10	0-08-096246-7 / 0080962467
ISBN-13	978-0-08-096246-7 / 9780080962467

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