Anti-VEGF strategies - from antibodies to tyrosine kinase inhibitors: background and clinical development in human cancer

Tumour angiogenesis (formation of new blood vessels supporting tumour growth and metastasis) is a result of complex interactions between the tumour and the surrounding microenvironment. Targeting tumours with anti-angiogenic therapy remains an exciting area of preclinical and clinical studies. Although many significant advances have been achieved and the clinical use of anti-angiogenic drugs is now well recognized in many solid malignancies, these therapies fall short of their anticipated clinical benefits and leave many unanswered questions like exact mechanism of action, patients' selection and monitoring response to anti-angiogenic drugs. Tumour angiogenesis is controlled by complex signaling cascades and ongoing research into molecular mechanisms of tumour angiogenesis not only helps to understand its basic mechanisms but hopefully will identify new therapeutic targets. In 2012, both monoclonal antibodies and small molecule tyrosine kinase inhibitors remain the two major clinically useful therapeutic options that interfere with tumour angiogenesis in many solid malignancies.     

Angiogenesis - Research Frontiers. A Basic Science Conference of the New York Academy of Medicine

Angiogenesis, the development of new blood vessels, is essential for both tumour growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenic process and its regulation have led to the discovery of a variety of targets for therapeutic intervention. The potential application of these angiogenic inhibitors is currently under intense preclinical and clinical investigation. Compelling evidence suggests that vascular endothelial growth factors (VEGFs) and their receptors play critical roles in tumour-associated angiogenesis. Tumour homing factors will drive the growth of new vessels, neoangiogenesis, to satisfy the demands of the growing tumour. By attacking the angiogenic process the tumour will be starved for oxygen and nutrients, thus impairing its growth. This has been demonstrated in a variety of animal tumour models in which disabling the function of VEGF or its receptor was shown to inhibit both tumour growth and metastasis. The New York Academy of Medicine organised a day-long meeting to discuss emerging ideas, currently available in vitro and animal models and evaluation of these therapies during their preclinical development and in clinical trials.     

Angiogenesis-research frontiers. A basic science conference of the New York Academy of Medicine

Angiogenesis, the development of new blood vessels, is essential for both tumour growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenic process and its regulation have led to the discovery of a variety of targets for therapeutic intervention. The potential application of these angiogenic inhibitors is currently under intense preclinical and clinical investigation. Compelling evidence suggests that vascular endothelial growth factors (VEGFs) and their receptors play critical roles in tumour-associated angiogenesis. Tumour homing factors will drive the growth of new vessels, neoangiogenesis, to satisfy the demands of the growing tumour. By attacking the angiogenic process the tumour will he starved for oxygen and nutrients, thus impairing its growth. This has been demonstrated in a variety of animal tumour models in which disabling the function of VEGF or its receptor was shown to inhibit both tumour growth and metastasis. The New York Academy of Medicine organised a day-long meeting to discuss emerging ideas, currently available in vitro and animal models and evaluation of these therapies during their preclinical development and in clinical trials.     

Apoptotic potency of angiostatic compounds in the treatment of cancer

When tumours outgrow their vascular supply, they become hypoxic because of nutrient deficiency. This increases the expression and secretion of proangiogenic factors, like vascular endothelial growth factor (VEGF), leading to the activation of endothelial cells. The activated endothelial cells migrate, proliferate and form new blood vessels, resulting in increased tumour growth. This process is called tumour angiogenesis. Inhibiting tumour angiogenesis and therefore tumour growth is a well known concept in the treatment of cancer, such as hepatocellular carcinoma (HCC). This can be done by endogenous angiogenesis inhibitors, like angiostatin and its derivates. These are known to affect endothelial cell functions including the induction of apoptosis. The impact of these angiostatic factors on the cell is manifold. This also applies for so called small molecules, which affect tyrosine kinases such as receptors or intracellular signal transduction proteins. Other approaches, like monoclonal antibodies, target a single molecule, mainly VEGF, to inhibit receptor binding and downstream signal transduction. Gene silencing, mainly via RNA interference (RNAi) intervenes on RNAlevel, leading to reduced gene expression and protein secretion. Due to intense research in this field, there is rising evidence that also tumour cells themselves are influenced by angiostatic treatment approaches and the underlying molecular mechanisms are more and more revealed. Here we give a (short) review regarding the pro-apoptotic potency of antiangiogenic compounds like angiostatic molecules, sequestering antibodies, small molecules and RNAi approaches targeting endothelial and tumour cell survival to inhibit angiogenesis and tumour growth.     

Angiogenesis as a therapeutic target in arthritis: lessons from oncology

Rheumatoid arthritis (RA) is a chronic disabling autoimmune inflammatory disease of unknown aetiology with a prevalence of about 1% in most parts of the world. As a result of the debilitating nature of the disease, sufferers struggle with the simple activities of daily living and frequently fail to remain in full time employment. Furthermore, the mortality associated with the disease is equivalent to that seen in triple vessel coronary artery disease. Over the 10-15 years, advances in understanding the mechanisms of RA pathogenesis based on studies of human cells and animal models of arthritis have led to the identification of new targets for therapeutic intervention. Despite these advances, a significant proportion of patients continue to exhibit disease which is refractory to such therapy. As an alternative to anti-cytokine therapy, formation of new blood vessels ('angiogenesis') represents a potentially attractive target for therapy in RA. Angiogenesis has been a putative target in cancer since it was first linked to tumour growth and metastases in the 1970s. A number of significant advances have been made in the development of anti-cancer therapy using such an approach. This review focuses on the potential for targeting angiogenesis in RA, building upon the experience of angiogenesis inhibition in the oncological setting. Through this we hope to emphasise the potential value of anti-angiogenic therapy in RA and identify future directions for optimising treatment of this disabling disease.     

Antiangiogenic drugs: current knowledge and new approaches to cancer therapy

Angiogenesis--process of new blood-vessel growth from existing vasculature--is an integral part of both normal developmental processes and numerous pathologies such as cancer, ischemic diseases and chronic inflammation. Angiogenesis plays a crucial role facilitating tumour growth and the metastatic process, and it is the result of a dynamic balance between proangiogenic and antiangiogenic factors. The potential to block tumour growth and metastases by angiogenesis inhibition represents an intriguing approach to the cancer treatment. Angiogenesis continues to be a topic of major scientific interest; and there are currently more antiangiogenic drugs in cancer clinical trials than those that fit into any other mechanistic category. Based on preclinical studies, researchers believe that targeting the blood vessels which support tumour growth could help treatment of a broad range of cancers. Angiogenic factors or their receptors, endothelial cell proliferation, matrix metalloproteinases or endothelial cell adhesion, are the main targets of an increasing number of clinical trials approved to test the tolerance and therapeutic efficacy of antiangiogenic agents. Unfortunately, contrary to initial expectations, it has been described that antiangiogenic treatment can cause different toxicities in cancer patients. The purpose of this article is to provide an overview of current attempts to inhibit tumour angiogenesis for cancer therapy.     

Chemokines: key players in cancer

SUMMARY

Chemokines are a family of low molecular weight (8-10kDa) pro-inflammatory cytokines, which bind to G-protein coupled receptors. Their primary function is chemoattraction and activation of specific leucocytes in various immuno-inflammatory responses. However, new research suggests that they are key players in cancer being involved in the neoplastic transformation of cells, promotion of aberrant angiogenesis, tumour clonal expansion and growth, passage through the extracellular matrix (ECM), intravasation into blood vessels or lymphatics and the non-random homing of tumour metastasis to specific sites. In view of the increasing significance of chemokines and their receptors in cancers of a variety of types, manipulation of this signalling pathway may be important in the development of new anticancer agents. This review provides an overview of recent research advances in this field and examines the potential therapeutic benefits future developments may bring.     

Chemokines: key players in cancer

Chemokines are a family of low molecular weight (8-10 kDa) pro-inflammatory cytokines, which bind to G-protein coupled receptors. Their primary function is chemoattraction and activation of specific leucocytes in various immuno-inflammatory responses. However, new research suggests that they are key players in cancer being involved in the neoplastic transformation of cells, promotion of aberrant angiogenesis, tumour clonal expansion and growth, passage through the extracellular matrix (ECM), intravasation into blood vessels or lymphatics and the non-random homing of tumour metastasis to specific sites. In view of the increasing significance of chemokines and their receptors in cancers of a variety of types, manipulation of this signalling pathway may be important in the development of new anticancer agents. This review provides an overview of recent research advances in this field and examines the potential therapeutic benefits future developments may bring.     

Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales

Angiogenesis, a process of new blood vessel formation, is a prerequisite for tumour growth to supply the proliferating tumour with oxygen and nutrients. The angiogenic process may contribute to tumour progression, invasion and metastasis, and is generally accepted as an indicator of tumour prognosis. Therefore, targeting tumour angiogenesis has become of high clinical relevance. The current review aimed to highlight mechanistic details of anti-angiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumour micro-environment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer.     

Intravital imaging of tumour vascular networks using multi-photon fluorescence microscopy

The blood supply of solid tumours affects the outcome of treatment via its influence on the microenvironment of tumour cells and drug delivery. In addition, tumour blood vessels are an important target for cancer therapy. Intravital microscopy of tumours growing in 'window chambers' in animal models provides a means of directly investigating tumour angiogenesis and vascular response to treatment, in terms of both the morphology of blood vessel networks and the function of individual vessels. These techniques allow repeated measurements of the same tumour. Recently, multi-photon fluorescence microscopy techniques have been applied to these model systems to obtain 3D images of the tumour vasculature, whilst simultaneously avoiding some of the problems associated with the use of conventional fluorescence microscopy in living tissues. Here, we review the current status of this work and provide some examples of its use for studying the dynamics of tumour angiogenesis and vascular function.     

Clinical development of angiogenesis inhibitors to vascular endothelial growth factor and its receptors as cancer therapeutics

Angiogenesis, the formation of new blood vessels, is essential for both tumor growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenesis process and its regulation have led to the discovery of a variety of pharmaceutical agents with anti-angiogenic activity. The potential application of these angiogenesis inhibitors is currently under intense clinical investigation. Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play critical roles in tumor-associated angiogenesis, and that they represent potential targets for therapeutic intervention. This has been demonstrated in a variety of animal tumor models in which disabling the function of VEGF and its receptors was shown to inhibit both tumor growth and metastasis. A number of agents designed specifically for targeting VEGF and/or its receptors are being evaluated in various clinical trials in cancer patients. This review will discuss the biology of the VEGF and its receptors, the mechanisms of action as well as the current status in clinical development of antagonistic agents to VEGF and its receptors. Included in this review are antagonistic antibodies, ribozymes, immunotoxins, and synthetic small molecular inhibitors.     

Beyond 5-fluorouracil: new horizons in systemic therapy for advanced colorectal cancer

Worldwide, colorectal cancer is a common cancer and a major cause of morbidity and mortality. Patients frequently present with, or later develop, metastatic disease. Median survival with supportive care alone is ～ 6 – 8 months. However, a number of recent developments have greatly increased the range of therapeutic options, improving median survival to > 20 months. Cytotoxic agents such as capecitabine, irinotecan and oxaliplatin are now established treatment strategies. In parallel, an improved understanding of tumour biology has led to the development of non-cytotoxic targeted therapies. Examples include bevacizumab (targeting tumour angiogenesis) and cetuximab (targeting the epidermal growth factor receptor). These agents have recently been incorporated into standard management. This paper reviews these and other advances in the care of patients with advanced colorectal cancer and discusses a number of agents that are currently under development.     

Beyond 5-fluorouracil: new horizons in systemic therapy for advanced colorectal cancer

Worldwide, colorectal cancer is a common cancer and a major cause of morbidity and mortality. Patients frequently present with, or later develop, metastatic disease. Median survival with supportive care alone is approximately 6 - 8 months. However, a number of recent developments have greatly increased the range of therapeutic options, improving median survival to > 20 months. Cytotoxic agents such as capecitabine, irinotecan and oxaliplatin are now established treatment strategies. In parallel, an improved understanding of tumour biology has led to the development of non-cytotoxic targeted therapies. Examples include bevacizumab (targeting tumour angiogenesis) and cetuximab (targeting the epidermal growth factor receptor). These agents have recently been incorporated into standard management. This paper reviews these and other advances in the care of patients with advanced colorectal cancer and discusses a number of agents that are currently under development.     

Antiangiogenesis drug design: multiple pathways targeting tumor vasculature

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.     

Endothelin-1 and angiogenesis in cancer

Tumours require oxygenation, nutrition and a route for dissemination. This necessitates the development of new vessels or angiogenesis. High levels of new vessel development are indicators of poor prognosis in cancer; they also provide new avenues of anti-tumour therapy. Angiogenesis in cancer produces structurally different vessels from angiogenesis in wound healing and inflammation. This article reviews the differences between vessels in tumour angiogenesis and normal angiogenesis. The main focus of the article is the role of the vasoactive peptide endothelin-1 (ET-1) in tumour angiogenesis. The role of ET-1 in tumour development is reviewed, before the direct and indirect effects of ET-1 in angiogenesis are examined. ET-1 has a direct angiogenic effect on endothelial and peri-vascular cells. It also has an indirect action through the increased release of the potent pro-angiogenic substance vascular endothelial growth factor (VEGF), via hypoxia inducible factor-1. ET-1 also indirectly stimulates angiogenesis by stimulating fibroblasts and cancer cells to produce pro-angiogenic proteases. ET-1 is a novel stimulator of tumour angiogenesis and warrants further examination as an anti-angiogenic treatment target.     

RGD peptide-based non-viral gene delivery vectors targeting integrin αvβ3 for cancer therapy

Integrin α_vβ₃ is restrictedly expressed on angiogenic blood vessels and tumour cells. It plays a key role in angiogenesis for tumour growth and metastasis. RGD peptide can specifically recognise the integrin α_vβ₃, which serves as targeted molecular for anti-angiogenesis strategies. Therefore, the targeted delivery of therapeutics by RGD peptide-based non-viral vectors to tumour vasculature and tumour cells is recognised as a promising approach for treating cancer. In this review, we illustrate the interaction between RGD peptide and integrin α_vβ₃ from different perspectives. Meanwhile, four types of RGD peptide-based non-viral gene delivery vectors for cancer therapy, including RGD-based cationic polymers, lipids, peptides and hybrid systems, are summarised. The aim is to particularly highlight the enhanced therapeutic effects and specific targeting ability exhibited by these vectors for cancer gene therapy both in vitro and in vivo.     

Angiopoietin/Tie receptor system: emerging targets for therapeutic angiogenesis and anti-angiogenic therapy

Balanced regulation of endothelial cell function and co-ordination of endothelial cells and periendothelial support cells by angiogenic growth factors and cell type-specific receptor tyrosine kinases is crucially involved in physiological angiogenesis. Disturbance of this fine-tuned balance is associated with disease-related neoangiogenesis, such as in tumour angiogenesis or in retinopathy, or in insufficient angiogenesis in occlusive vascular disease. In addition to the well known function of vascular endothelial growth factor (VEGF) as an endothelial cell-specific angiogenesis inducer and survival factor, recent studies on angiopoietins and their receptors have provided insight into the interplay of these endothelium-specific ligand-receptor systems in formation, maintenance and remodelling of the vasculature. Knowledge of the mechanisms by which these ligand-receptor systems are involved in regulation of the interaction of endothelial cells and their periendothelial support cells opens new opportunities for therapeutic angiogenesis to induce formation of functional blood vessels in occlusive disease, as well as to complement and/or enhance current anti-VEGF-based strategies for anti-angiogenic therapy.     

Patent focus on cancer chemotherapeutics V. Angiogenesis agents: September 2001 – August 2002

Angiogenesis refers to the formation of new capillaries from existing blood vessels and is believed to be a key process in tumour growth. Angiogenesis inhibition represents an active area of cancer drug discovery, with several agents and approaches now entering late stage clinical development. This review summarises the key aspects of recent patent applications relating to cancer chemotherapy and drug discovery that involve inhibition or modulation of angiogenesis. The review includes applications that have been published between September 2001 and August 2002. In particular, the review focuses on the approaches aimed at growth factor targets, such as angiopoietin, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF).     

Review article: angiogenesis soluble factors as liver disease markers

Angiogenesis is the formation of new blood vessels from pre-existing ones; it has been studied at the molecular level in different pathologies and is currently considered a promising novel therapeutic target in cancer. Recently, the use of angiogenesis soluble factors as markers of tumour growth has been investigated. The knowledge gained has led to test their use as therapeutic agents. Additionally, angiogenesis soluble factors could be used for the follow-up of pathologies that currently require monitoring with invasive techniques, like chronic viral hepatitis or renal and haematological diseases. The different factors have been described in multiple studies. In some cases, such as hepatocellular carcinoma, a potential use as prognostic markers has been suggested.     

Patent focus on cancer chemotherapeutics. III Angiogenesis agents: October 2000 – March 2001

Angiogenesis refers to the formation of new blood vessels from existing blood vessels, a process that is believed to be a key requirement for tumour growth and metastasis. Angiogenesis inhibition represents a new approach to cancer chemotherapy and several agents and approaches are now entering late clinical development. This review summarises the key aspects of recent patent applications referring to cancer chemotherapy and cancer drug discovery that involve inhibition or reduction of angiogenesis. The review covers the main mechanism-based approaches such as MMPIs, inhibitors of the growth factor signalling pathways, integrin antagonists and urokinase inhibitors. Additional sections relating to vascular damaging agents, endogenous inhibitors and selected natural products are also included. The scope includes applications that published from October 2000 through March 2001.