Rebecca Suk Heist, MD, MPH
Department of Oncology
Massachusetts General Hospital Cancer Center, Boston, Massachusetts
Numerous drugs that target the vascular endothelial growth factor (VEGF) pathway are now in clinical development and a few are approved for use, including bevacizumab, a monoclonal antibody to VEGF-A, which is approved for use in lung cancer. Why would targeting blood vessel formation in general, and VEGF in particular, be a successful strategy in treating cancer? This concept was not always as readily accepted as it is today, and certainly there were skeptics when Folkman hypothesized in 1971 that blocking the angiogenic pathway could be a therapeutic strategy in cancer.11 Since then, however, a growing body of work has demonstrated the importance of angiogenesis in tumor formation and growth. This work is seeing fruition now as VEGF pathway inhibitors come to clinical use.
Normal vasculature is relatively quiescent in adults; only 0.01% of endothelial cells are undergoing cell division at any time. New blood vessel formation is a highly ordered and complex system, requiring multiple tightly controlled steps: degradation of basement membrane, stromal invasion, proliferation of endothelial cells, and formation of capillary lumen.12 Although normal physiologic conditions exist under which angiogenesis occurs (e.g., the female reproductive cycle and wound healing), most angiogenesis in adults occurs in the context of pathologic conditions.12
Much work has been done to understand tumor angiogenesis. Angiogenesis seems to be importantfor both tumor growth and metastasis.13 In the absence of blood vessels, tumor growth is restricted. In a classic experiment where tumor cells were placed in an avascular setting and prevented from accessing blood vessels, the maximum diameter attained by the tumor was 0.4 mm.14 Without blood vessels supplying oxygen and nutrients to sustain cell growth, tumors cannot continue to grow. In addition, the development of metastatic disease requires that tumor cells travel via the bloodstream to seed distant sites hematogenously. A critical part of carcinogenesis, or acquiring a tumor phenotype, then, is initiating, or turning on the "switch" to activate angiogenesis.15 This activation seems to be an early step in tumor development.11
It is hypothesized that numerous proangiogenic and antiangiogenic factors closely interact to regulate and ultimately determine when the "angiogenic switch" is turned on. Figure 1 illustrates the balance between factors that activate and inhibit angiogenesis. Once the "angiogenic switch" is turned on, blood vessel formation is an integral part of continued tumor development. Tumor-associated blood vessels are markedly different from normal vasculature and are characterized by disorganized, tortuous, leaky vessels with chaotic blood flow. This dysregulated blood flow allows for hypoxic and acidic regions within tumors, which may select for more malignant clones and compromise delivery of anticancer drugs to the tumor.16
Targeting tumor angiogenesis is an attractive strategy for anticancer therapy. Normal angiogenesis in adults occurs in only a few limited situations; however, tumors require angiogenesis to grow, which allows for selectivity of action of the antiangiogenic drug against tumors rather than normal tissue. In addition, characteristics of tumor vasculature seem to be shared across various tumor types, and it is hypothesized that the genetic stability of endothelial cells makes resistance less likely.17
It is important to note, however, that the mechanism by which antiangiogenic therapy acts may be more complex than merely limiting access to blood supply by a tumor. The concept of using antiangiogenic therapy to normalize tumor vasculature by pruning and remodeling leaky abnormal vasculature, decrease interstitial fluid pressure, increase tumor oxygenation, and enhance delivery of other anticancer drugs, may be an important mechanism of action.18
VEGF Pathway in Angiogenesis
VEGF has been identified as a critical component of the angiogenic pathway. VEGF inhibition is correlated with suppression of tumor growth and angiogenesis.19-21 VEGF expression in tumors is associated with high microvessel counts and histologic dedifferentiation.22-24 Figure 2 illustrates the role of VEGF and VEGFR in tumor angiogenesis. VEGF has been found to be overexpressed in many tumor types, and increasing vascularity of tumors (measured by microvessel count) and VEGF expression may be associated with worse prognosis in a wide variety of malignancies, including lung cancer.25-29
The VEGF family of glycoproteins includes VEGF-A (commonly called VEGF), VEGF-B, VEGF-C, VEGF-D, VEGF-E, PIGF-1, and PIGF-2.30 VEGF-A is critical to angiogenesis; in mice; loss of a single allele is embryonically lethal.31, 32 VEGF-B may play a role that is redundant to VEGF-A, whereas VEGF-C and VEGF-D are thought to be more involved in lymphangiogenesis.33Downstream effects are mediated via ligand binding to VEGF receptors (VEGFRs) (Figure 3), which ultimately leads to vascular and lymphatic endothelial cell proliferation, survival, and migration.25 Under physiologic conditions, VEGFR-2 is the receptor most closely tied to VEGF-A, but VEGFR-1 seems to also play a role in pathologic conditions.
Elucidation of key elements of the VEGF pathway has provided the framework for developing targeted therapies that inhibit VEGF signaling. Anti-VEGF strategies include antibodies to bind to VEGF and prevent binding to VEGFR, soluble VEGFRs that bind up VEGF ligand, and tyrosine kinase inhibitors of VEGFRs that prevent downstream activation and cell signaling. Bevacizumab was the first of the VEGF antagonists to be approved for clinical use in lung cancer, and numerous other drugs, several of which are discussed in the following sections, are currently in development.
Dr. Lynch: Do you think anti-VEGF treatments work because of direct effects on tumor cells or by targeting the endothelium?
Dr. Kim: I grapple with this concept all the time. Multiple theories have been put forth about whether endothelial cells or the vasculature are being targeted. We know that new vessel growth is affected, but what happens to existing vasculature with regard to stabilization is more hypothetical. The process of angiogenesis is difficult to simplify because of its multifactorial nature.
Dr. Lynch: Do you think the single-agent oral tyrosine kinase inhibitors, sunitinib and sorafenib, have the same mechanism of action as the anti-VEGF agents?
Dr. Socinski: We have an idea that the antibody has specificity to VEGF, whereas many of the multi- targeted kinases have a broader spectrum of activity. The challenge is knowing which targets are impor- tant and which are vital to the activity of the kinases. It would be interesting to combine the kinases with bevacizumab to see if a dual blockade of the pathway conferred any advantage, assuming of course, that toxicity would be acceptable.