Elsevier

Biochemical Pharmacology

Volume 89, Issue 2, 15 May 2014, Pages 162-170
Biochemical Pharmacology

Commentary
Metabolic effects of antiangiogenic drugs in tumors: Therapeutic implications

https://doi.org/10.1016/j.bcp.2014.02.018Get rights and content

Abstract

Antiangiogenic therapy has become a mainstay of cancer therapeutics, but clinical responses are generally short-term owing to the development of secondary resistance. Tumor starvation by antiangiogenic drugs is largely attributed to increased hypoxia and impaired nutrients supply, suggesting that angiogenesis inhibition causes remarkable metabolic perturbations in the tumor microenvironment. We review here recent acquisitions concerning metabolic effects of angiogenesis blockade in tumors and discuss the possibility that some metabolic features of tumor cells – i.e. their dependency from glucose as primary energy substrate – might affect tumor responses to anti-vascular endothelial growth factor treatment. Moreover, we discuss the hypothesis that anti-angiogenic therapy might foster metabolic evolution of tumors. The therapeutic implications of this hypothesis will be discussed further here.

Introduction

Angiogenesis is a tightly regulated biological process through which new blood vessels are generated from pre-existing ones. Following seminal observations by Folkman and other investigators in the 1970s [1], angiogenesis became a vivid area in cancer research and stimulated the search for conceptually new treatments. The identification of vascular endothelial growth factor (VEGF) as a key driver of the angiogenic process [2] has converted the VEGF/VEGF receptor (VEGFR) signaling pathway into an attractive therapeutic target. VEGF blockers belong to two broad categories including (I) VEGF ligand-blocking drugs and (II) drugs blocking VEGFR signaling. Not surprisingly, given the redundancy of factors involved in the regulation of the angiogenic process, also other angiogenic factors and signaling pathways – such as fibroblast growth factors (FGFs) and angiopoietins – have been considered as potential therapeutic targets [3], [4]. After a decade of clinical research, we are currently at a critical point in the development of antiangiogenic drugs for cancer, as their therapeutic activity in patients has been substantially lower than expected based on preclinical findings. The development of assays to interrogate the dependence of individual tumors from any of these key angiogenic pathways will certainly be fundamental to personalize and possibly improve efficacy of antiangiogenic therapy.

Since the field of angiogenesis inhibitors is very large and the topic has been extensively reviewed elsewhere [5], [6], [7], we will briefly overview only a fraction of the antiangiogenic agents available, focusing on those in late stage clinical trials or approved by the regulatory agencies, being aware that more antiangiogenic drugs will enter the clinical arena in the coming years. A summary of the main characteristics and pharmacologic targets of these drugs is presented in Table 1, whereas their structure is shown in Fig. 1. Next, we will review literature linking antiangiogenic therapy to tumor metabolism, explain why we consider this an interesting area of investigation and outline possible therapeutic implications of these studies.

Section snippets

Bevacizumab

A recombinant humanized monoclonal anti-VEGF antibody which binds to all active isoforms of VEGF-A and neutralizes their activity by preventing binding of VEGF to its receptors. Based on the positive outcome of several phase III clinical trials, in the United States (U.S.) bevacizumab was approved for four types of cancer including metastatic renal cell carcinoma (mRCC), metastatic colorectal cancer (mCRC), non-small cell lung cancer (NSCLC) and recurrent glioblastoma (rGBM) [8]. In Europe,

Vascular responses to antiangiogenic therapies

The rationale of antiangiogenic therapy is grounded on the concept of starving the tumor of oxygen and nutrients, thereby limiting the capacity of tumors to grow. Since most of these drugs, and bevacizumab in particular, generally lack direct cytotoxic or cytostatic effects on tumor cells, their therapeutic activity has been attributed to effects on the tumor microenvironment. The best characterized effect of many of these drugs is induction of hypoxia, which has been observed in many

Metabolic effects of antiangiogenic therapy: Looking beyond hypoxia

As anticipated above, the best recognized metabolic effect of antiangiogenic therapy is hypoxia, which leads to stabilization of HIF-1, a transcriptional factor which coordinates adaptation of cells to hypoxic conditions by modulation of gene sets involved in the regulation of cell proliferation, apoptosis, angiogenesis and metabolism [40]. Once activated, HIF-1 induces the transcription of genes encoding glucose transporters and most glycolytic enzymes. In addition, HIF-1 activates the

Metabolic evolution of tumors treated with anti-VEGF therapy

One of the intriguing questions related to the metabolic changes caused by antiangiogenic therapy is whether they are transient or stable (Fig. 3). At least some of these metabolic changes are indeed HIF-1α-driven and therefore could reflect adaptation to the hypoxic microenvironment rather than stable metabolic changes in tumor cells. Increased expression of glycolysis-associated markers following bevacizumab has been observed in previous studies [55], but it was considered to depend on

Antiangiogenic therapy may sensitize tumors to glycolytic metabolism-targeting drugs

Conceivably, alteration of glucose metabolism in tumors treated with antiangiogenic drugs may render them more likely to respond to drugs targeting the glycolytic metabolism. In this respect, several “druggable” targets have been identified along the glycolytic pathway [66], but there is still a paucity of investigations on the potential advantage of combining antiangiogenic therapies with agents counteracting glycolysis. One problem could be efficient delivery of the drugs to tumors, given the

Conclusions

Understanding metabolic perturbations associated with administration of antiangiogenic drugs is a novel area of investigation, which will greatly profit of advanced technologies such as hyperpolarized MRI and other innovative imaging techniques, which enable serial evaluation of metabolic parameters. Therapeutic targeting of dis-regulated metabolic pathways, such as glycolysis, is potentially a very attractive strategy because it takes advantage of increased dependence of tumor cells on

Review criteria

Data for this Review were obtained by searching the PubMed database before 1 December 2013 using search terms including but not restricted to “antiangiogenic therapy”, “VEGF inhibitor”, “VEGF blockade”, “anti-VEGF therapy”, “bevacizumab”, “sunitinib”, “mass spectrometry”, “magnetic resonance spectroscopy”, “PET”, “metabolism”, “glycolysis”. Reference lists from identified articles were also searched for additional articles. Only full-text articles published in English were considered.

Conflict of interest statement

The Authors declare no conflict of interest.

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    M.S was a recipient of the Erasmus Mundus Fellowship (Al-Fihri Program).

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