Journal of Clinical Oncology, Vol 18, No 21S (November 1 Supplement),
2000: 45s-46s
© 2000 American Society for Clinical Oncology
Vascular Endothelial Growth Factor as a Target for Antiangiogenic Therapy
By Michael S. Gordon
From the University of Arizona College of Medicine, Phoenix, AZ.
Address reprint requests to Michael S. Gordon, MD, University of Arizona Health Sciences Center, 4001 North 3rd St, Suite 415, Phoenix, AZ 85012; email msgordon{at}u.arizona.edu
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INTRODUCTION
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ANGIOGENESIS AS A physiologic process is tightly regulated by a family of pro- and antiangiogenic factors. Many of these agents, such as vascular endothelial growth factor (VEGF), are highly specific for the endothelial compartment, whereas others (such as the matrix metalloproteinases) have various nonangiogenic activities. As a physiologic process, angiogenesis plays a role in embryonic development and wound healing. It is in the evolution of cancer, however, that we see angiogenesis play a central role in the malignant process as well as the development of metastatic lesions.
As an important component of malignant progression, angiogenesis is involved in the initial growth of primary tumors. This relationship was recognized by Folkman,1 who hypothesized that growth of a primary tumor was dependent on an associated increase in the tumor’s endothelial compartment. More recent information2,3 has demonstrated that the "dormancy" of micrometastatic deposits is similarly dependent on angiogenesis and that a balanced rate of proliferation and apoptosis can be tipped in favor of cell growth when the tumor evolves an angiogenic phenotype.
The process of angiogenesis therefore represents a balance between the proangiogenic factors stimulating the process and the natural inhibitors of angiogenesis. When the balance tips in favor of the development of new vessels, either by an increase in angiogenic stimuli, a decrease in antiangiogenic factors, or some combination of the two, the process proceeds at a brisker rate.
The angiogenic process is characterized by a number of independent but interlinked processes. These include the dissolution of the basement membrane, the induction of endothelial cell proliferation and migration, and the resolution of the process with microtubular formation. As a result of this stepwise progression, antiangiogenic therapy can be developed against a specific aspect of the process.
The value of antiangiogenic therapy is as yet unclear. The effect of agents, designed to inhibit new vessel formation, on established tumor vasculature cannot be predicted. This is particularly true since most preclinical models, on which we base clinical strategies, reflect young, newly developed vessels as opposed to the more longstanding tumoral vessels seen in human cancers. Hence, the principal use of the agents may be best envisioned to be in combination with standard therapy as opposed to single-agent therapy. This is particularly true because antitumor therapy in single-agent trials has not been frequently seen.
As a target, VEGF represents a factor whose expression has been correlated with both relapse-free and overall survival in patients with a variety of malignancies. Antiangiogenic approaches targeting this molecule have included the development of monoclonal antibodies to VEGF, specific inhibitors of the principle VEGF receptor (KDR receptor), and more broad-based tyrosine kinase receptor antagonists. These approaches have been similarly effective in preclinical models and are currently working their way through different phases of clinical development.
One consideration regarding the potential use of antiangiogenic therapy highlights the concept of tumor dormancy. If in fact a significant reduction in tumoral vascularity can induce a state of tumor dormancy, is it possible that the ability to actually "cure" early malignancies relates to the induction of a dormant state and might the use of antiangiogenic therapy in combination with standard adjuvant treatment produce greater numbers of long-term remissions? The concept, outlined in Fig 1, suggests that the effect of chemotherapy alone may reduce the tumor load but not have a significant enough impact on tumor vascularity to induce durable remissions. The addition of an antiangiogenic agent may result in a significant enough decrease in tumoral vessels to allow a more durable response.
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Fig 1. Addition of an antiangiogenic agent may result in a significant enough decrease in tumoral vessels to allow a more durable response.
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REFERENCES
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1.
Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med 285: 1182-1186, 1971
2.
Hahnfeldt P, Panigrahy D, Folkman J, et al: Tumor development under angiogenic signaling: A dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res 59: 4770-4775, 1999[Abstract/Free Full Text]
3.
Barnhill RL, Piepkorn MW, Cochran AJ, et al: Tumor vascularity, proliferation, and apoptosis in human melanoma micrometastases and macrometastases. Arch Dermatol 134: 991-994, 1998[Abstract/Free Full Text]
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INTRODUCTION
REFERENCES
