Benefits of Vascular Normalization Are Dose and Time Dependent—Letter
Authors: Yuhui Huang, Triantafyllos Stylianopoulos, Dan G. Duda, Dai Fukumura, Rakesh K. Jain
Journal: Cancer Research (2013)

Arjaans and colleagues reported that treatment with the anti-VEGF antibody bevacizumab hampers antibody uptake in an ectopic xenograft model of human ovarian cancer in mice (1). They found that bevacizumab decreased vessel number and increased pericyte coverage and concluded that treatment-induced normalization is detrimental for antibody delivery. This conclusion is not supported by their data and is in disagreement with the existing literature (2–4).Vascular normalization after antiangiogenic therapy could explain the seemingly paradoxical synergism between antiangiogenic agents and concurrent systemic anticancer therapies (2). The vascular normalization paradigm was originally described to have four key elements: structural normalization, functional normalization, the transient nature of the effects, and the dose dependence (Fig. 1), with functional normalization being the most important element (2).Arjaans and colleagues used a relatively high dose of bevacizumab and detected structural changes consistent with structural vascular normalization. However, they present no evidence that bevacizumab functionally normalized tumor blood vessels, nor do they mention when antibody treatment was delivered with respect to the vascular normalization time window. These deficiencies notwithstanding, the study raises an important question: Could antiangiogenic therapy impair the delivery of antibodies? The answer is likely yes, as the normalization time window may narrow or even disappear when antiangiogenic agents are dosed to potentiate antivascular effects. Antivascular effects could lead to a transient delay in tumor growth. The remaining vessels may be pericyte-covered, but because these treatments greatly reduce the number of functional vessels, they could potentially hinder the delivery of drugs at that time—a status referred to as "inadequate" rather than "normalized" vasculature (2, 5). This scenario is more consistent with the report by Arjaans and colleagues (1), that is, a predominant antivascular rather than vascular normalizing effect of bevacizumab in their experimental setting. The potential of antiangiogenics to produce both vascular normalizing and antivascular effects is of great clinical relevance for how these drugs should be combined with other therapeutics. Indeed, clinical studies have shown that the addition of high-dose bevacizumab does not improve overall survival when combined with chemotherapeutics in some cancers, such as ovarian or breast cancers. Therefore, it is high time we design better ways for using antiangiogenic therapy in the clinic. Our recent work suggests that anti-VEGFR2 antibody (DC101) treatment can normalize orthotopic tumor vasculature and enhance the delivery of anticancer agents in a dose- and time-dependent manner (Fig. 2; refs. 3, 4). It also shows that these benefits may be lost when using high-dose antiangiogenic therapy due to pronounced antivascular effects. Thus, optimizing combinations of antiangiogenic agents with anticancer treatments will require imaging and/or circulating biomarkers based on an in-depth understanding of the dynamics of the tumor vascular response, in particular the balance between vascular normalizing and antivascular effects.See the Response, p. 7147D.G. Duda is a consultant/advisory board member for Hexal. R.K. Jain is on the board of Xtuit, H&Q Healthcare Investors, and H&Q Life Sciences Investors has grants from MedImmune, and Roche, has ownership interest (including patents) in Enlight, Xtuit, SynDevRx, and is a consultant/advisory board member for Noxxon Pharma, Zyngenia, WebMD, Enlight, and SynDevRx. No potential conflicts of interest were disclosed by the other authors.