Vascular remodeling and clinical resistance to antiangiogenic cancer therapy

Abstract

When first conceived, antiangiogenic therapy for cancer offered the possibility of universal efficacy, low toxicity, and little possibility of resistance. Blockade of the vascular endothelial growth factor (VEGF) pathway has yielded the most promising results both in animal models and in patients. However, resistance to VEGF blockade has been found even when given in combination with chemotherapy or other antiangiogenic agents. This resistance is associated with remodeled vasculature and with increased expression of angiogenic factors, such as PDGF-B and angiopoietin-1, which may contribute to vessel stabilization. Future efforts must be directed towards the identification of factors associated with vascular remodeling in order to improve the efficacy of antiangiogenic therapy.

Introduction

In 1971, Judah Folkman proposed that, since growth of solid tumors requires neovascularization, prevention of new vessel sprouts or “antiangiogenesis” could result in tumor dormancy and thus be a novel cancer therapy (Folkman, 1971). As the concept matured, Folkman and others further hypothesized that if “genetically stable” endothelial cells were stimulated to proliferate by the pathologic tumor environment, then this activated but normal endothelium might represent a unique and exquisitely selective target (Kerbel, 1991, Boehm and Folkman, 1997, Kerbel and Folkman, 2002). Most adult endothelial cells, like bone marrow stem cells, divide infrequently, and are thus unlikely to develop selectable genetic mutations. Targeting of endothelial cells seemed to offer promise for efficacy, low toxicity, and little or no potential for resistance.

Over 30 years later, this hypothesis has generated an extraordinary body of research, resulting in an enormous wave of antiangiogenic agents that are now being delivered to patients. Most of these new agents target pro-angiogenic growth factors, principally vascular endothelial growth factor (VEGF), or exploit the tumor-suppressive effects of endogenous inhibitors of angiogenesis. Bevacizumab (Avastin), an anti-VEGF monoclonal antibody, was recently granted FDA approval for use in metastatic colon cancer, based on clinical trials showing significantly increased time to progression (Kabbinavar et al., 2003, Hurwitz et al., 2004). Nonetheless, cure of remains elusive. Cancer patients and physicians are confronting a phenomenon with which they are all too familiar: transient, incomplete responses or temporary disease stability, followed by inevitable tumor regrowth. The mechanisms of tumor escape from antiangiogenic suppression are unknown. Thus, if the clinical promise of antiangiogenic strategies is to be fully realized, these biologic compensatory mechanisms must be better understood (Broxterman et al., 2003, Eichhorn et al., 2004). Current studies of the effects of ablating or attenuating tumor vasculature, and the implications of these responses for clinical regimens incorporating these agents, are the subject of this review. Because the best-validated antiangiogenic strategies target VEGF, we will focus primarily on the response of tumors and tumor vasculature to perturbation of VEGF signaling.