Tumoral angiogenesis: review of the literature

Tumoral angiogenesis is necessary for the growth of neoplasms and the production of metastasis. The vascular endothelial growth factor (VEGF) is a homodimeric heparin-binding glycoprotein that binds to VEGF-receptors and can induce endothelial cell mitosis, invasion, and eventually capillary tube formation. Bevacizumab, a humanized monoclonal antibody against VEGF, inhibits tumoral angiogenesis and may also improve the delivery of chemotherapy to the tumor mass. Some new antiangiogenic agents, called multi-kinase inhibitors (sorafenib and sunitinib), have also activity against other receptors, such as epidermal growth factor-receptor or platelet-derived growth factor-receptor. A new schedule of treatment (metronomic chemotherapy) also has antiangiogenic activity.     

Safety profile and tolerability of antiangiogenic agents in non-small-cell lung cancer

Recent advances in understanding the importance of angiogenesis to tumor growth and distant metastasis has driven the development of antiangiogenic therapies for the treatment of non-small-cell lung cancer (NSCLC). The anti-vascular endothelial growth factor (VEGF) monoclonal antibody, bevacizumab, is the only US Food and Drug Administration-approved antiangiogenic agent for advanced NSCLC. Accumulated safety data with bevacizumab in NSCLC shows that patients are at risk for hemorrhage, venous thromboembolism, hypertension, and proteinuria. Investigational agents that target VEGF via a different mechanism (such as aflibercept [VEGF Trap]) or simultaneously inhibit multiple molecular pathways involved in angiogenesis (ie, multitargeted tyrosine kinase inhibitors [TKIs]) and vascular disrupting agents (VDAs) that target existing tumor vasculature are in various stages of clinical development for NSCLC, and safety profiles are emerging for these classes of agents. This review describes the molecular rationale for targeting angiogenic pathways in anticancer therapy and summarizes safety and tolerability data from clinical trials of bevacizumab or aflibercept in combination with chemotherapy and the investigational TKIs and VDAs in patients who have advanced NSCLC.     

Examining the safety profile of angiogenesis inhibitors: implications for clinical practice

Dysregulation of angiogenesis in solid tumors enables tumor growth and metastasis. Receptors that mediate angiogenesis, and their ligands, have been identified; among these, vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase play a central role. In non-small cell lung cancer (NSCLC), clinical benefit has been shown with bevacizumab, which blocks VEGF binding to its receptors. In addition, small-molecule tyrosine kinase inhibitors are currently in clinical practice or development in several indications. The potential clinical benefit of antiangiogenic agents is accompanied by the need to understand their safety profiles, seek suitable combination regimens and identify patients able to tolerate one treatment over another. This is particularly relevant in cancers for which patients often present with advanced disease and suffer co-morbidities, requiring an agent that is both efficacious and well tolerated over long-term continuous treatment. Using literature from peer-reviewed journals, this review considers different antiangiogenic agents and their safety profiles, focusing on the potential impact of these data on the treatment of patients with NSCLC.     

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR-2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti-VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors.

Implications for Practice:

Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF-targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.     

Antiangiogenesis Therapy in Breast Cancer

Increased expression of the vascular endothelial growth factor (VEGF) is a poor prognostic factor in breast cancer, indicating that antiangiogenic therapies may improve outcomes. Novel antiangiogenic agents targeting the proangiogenic VEGF ligand and receptor tyrosine kinase inhibitors have been developed. Of these, bevacizumab, a humanized monoclonal antibody directed against VEGF, is very promising in breast cancer. A large phase 3 clinical trial demonstrated a statistically significant improvement in progression-free survival with the addition of bevacizumab to paclitaxel as first-line treatment of advanced breast cancer, establishing the benefit of antiangiogenic therapy in breast cancer. Additional studies of bevacizumab in the metastatic, adjuvant, and neoadjuvant settings are underway. Ongoing trials are also evaluating the efficacy of multitargeted tyrosine kinase inhibitors in advanced breast cancer. This article reviews the results of the key trials evaluating antiangiogenic agents in breast cancer with particular emphasis on bevacizumab and future directions of antiangiogenic therapy.     

Emerging antiangiogenic therapies for non-small-cell lung cancer

Lung cancer remains the leading cause of cancer-related deaths. Antiangiogenic therapy has increasingly been studied for advanced non-small-cell lung cancer (NSCLC). Bevacizumab is the only approved antiangiogenic agent for NSCLC and has shown progression-free survival benefits in large Phase III studies and an overall survival benefit in the Phase III E4599 trial in advanced nonsquamous NSCLC. New antiangiogenic treatment strategies are being evaluated that target multiple receptors within a family (VEGF receptor [VEGFR]-1, VEGFR-2) or multiple angiogenic pathways (targets VEGFR and PDGF receptor pathways), and agents that inhibit alternative mediators of angiogenesis (integrins and established vasculature). As data become available from ongoing studies, it will be important to determine how these new antiangiogenic agents will best fit into the current NSCLC treatment paradigm.     

Emerging antiangiogenic therapies for non-small-cell lung cancer

Lung cancer remains the leading cause of cancer-related deaths. Antiangiogenic therapy has increasingly been studied for advanced non-small-cell lung cancer (NSCLC). Bevacizumab is the only approved antiangiogenic agent for NSCLC and has shown progression-free survival benefits in large Phase III studies and an overall survival benefit in the Phase III E4599 trial in advanced nonsquamous NSCLC. New antiangiogenic treatment strategies are being evaluated that target multiple receptors within a family (VEGF receptor [VEGFR]-1, VEGFR-2) or multiple angiogenic pathways (targets VEGFR and PDGF receptor pathways), and agents that inhibit alternative mediators of angiogenesis (integrins and established vasculature). As data become available from ongoing studies, it will be important to determine how these new antiangiogenic agents will best fit into the current NSCLC treatment paradigm.     

Overexpression of VEGF121, but not VEGF165 or FGF-1, improves oxygenation in MCF-7 breast tumours

Vascular endothelial growth factor (VEGF) is an intensively studied molecule that has significant potential, both in stimulating angiogenesis and as a target for antiangiogenic approaches. We utilised MCF-7 breast cancer cells transfected with either of two of the major VEGF isoforms, VEGF(121) or VEGF(165), or fibroblast growth factor-1 (FGF-1) to distinguish the effects of these factors on tumour growth, vascular function, and oxygen delivery. While each transfectant demonstrated substantially increased tumorigenicity and growth rate compared to vector controls, only VEGF(121) produced a combination of significantly reduced total and perfused vessel spacing, as well as a corresponding reduction in overall tumour hypoxia. Such pathophysiological effects are of potential importance, since antiangiogenic agents designed to block VEGF isoforms could in turn result in the development of therapeutically unfavourable environments. If antiangiogenic agents are also combined with conventional therapies such as irradiation or chemotherapy, microregional deficiencies in oxygenation could play a key role in ultimate therapeutic success.     

Bevacizumab for advanced breast cancer

Tumor angiogenesis is essential for the growth and metastasis of solid tumors. In breast cancer, increased levels of vascular endothelial growth factor (VEGF) have been associated with poor prognosis in lymph node-positive and lymph node-negative patients. In addition to its prognostic significance, VEGF is now a validated target in the treatment of breast cancer. Bevacizumab, an anti-VEGF antibody, has demonstrated significant clinical benefit in several solid tumors. In this article the authors discuss the data pertaining to bevacizumab and other antiangiogenic agents for the treatment of patients who have advanced breast cancer.     

Reappraisal of the role of bevacizumab in the therapeutic strategy in advanced renal cell carcinoma

Increased understanding of the molecular pathophysiology of metastatic renal cell carcinoma (mRCC) has led to development of antiangiogenic therapies in the past 5 years that significantly improved the prognosis. Vascular endothelial growth factor (VEGF) is a major growth factor in tumor angiogenesis and is implicated in tumor progression of several types of cancer, including mRCC. Use of 2 distinct approaches resulted in clinical efficacy in blocking the VEGF pathway: small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib) and the humanized anti-VEGF monoclonal antibody bevacizumab that binds circulating VEGF and prevents activation of the VEGF receptor. In the 2 large phase III trials AVOREN and CALGB 90206, bevacizumab combined with interferon alfa demonstrated its efficacy as a first-line therapy in terms of progression-free survival. Nevertheless, in the era of targeted therapies, other studies are still needed to better obtain the maximal clinical benefit of bevacizumab. The aim of this overview is to report the current role of bevacizumab in the treatment of metastatic kidney cancer and to highlight possible combinations or sequential strategies that involve other targeted agents.     

Emerging Data with Antiangiogenic Therapies in Early and Advanced Non–Small-Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the United States. Patients treated with adjuvant chemotherapy have a 5-year survival rate of 25% to 70% depending on stage, whereas those with advanced disease have a median survival of approximately 8 months when treated with standard platinum-based therapy. Improvements in our understanding of cancer biology have led to the development of novel agents that more precisely affect the target of interest, allowing for a more rational approach to clinical trial design. Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in tumor growth and progression. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is the most studied antiangiogenic agent in patients with Non—Small-cell lung cancer (NSCLC). There was an improvement in overall survival when bevacizumab was combined with paclitaxel and carboplatin in patients with advanced NSCLC that was not seen when bevacizumab was combined with cisplatin and gemcitabine. Studies with bevacizumab in the adjuvant and advanced setting are ongoing in patients with NSCLC. Small-molecule inhibitors targeting the VEGF receptor and the tyrosine kinase receptor have also shown promise when combined with standard chemotherapy, but their role in the treatment of patients with NSCLC remains to be determined. This article reviews clinical trials that have incorporated antiangiogenic agents in the treatment of patients with NSCLC.     

The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors

Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.     

Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization, which plays an important role in the growth and progression of HCC. Angiogenesis provides a target for novel prognostic and therapeutic approaches to HCC. Assessment of microvessel density using immunohistochemical staining for specific endothelial cell markers such as CD34 has been shown to provide prognostic information independent of conventional pathological parameters in HCC patients. Recent studies have unveiled the important angiogenic factors involved in the regulation of angiogenesis in HCC, although the exact molecular pathways are far from clear. Current data suggest that vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis of HCC. Tumor expression of VEGF has been shown to correlate with tumor invasiveness and prognosis in patients with HCC. VEGF is an important molecular target for antiangiogenic therapy. Studies in animal models have demonstrated the efficacy of antiangiogenic agents such as anti-VEGF antibody and antagonists of VEGF receptors in suppressing hepatocarcinogenesis and growth of HCC. Antiangiogenic therapy has already entered clinical trials in HCC patients and holds the promise of providing an effective novel treatment for HCC, which is of great clinical significance because there is no existing effective systemic therapy for HCC.     

Overcoming resistance to antiangiogenic therapies

The concept of targeting new blood vessel formation, or angiogenesis, in tumors is an important advancement in cancer therapy, resulting, in part, from the development of such biologic agents as bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF)-A. The rationale for antiangiogenic therapy is based on the hypothesis that if tumors are limited in their capacity to obtain a new blood supply, so too is their capacity for growth and metastasis. Additional evidence suggests that pruning and/or "normalization" of irregular tumor vasculature and reduction of hypoxia may facilitate greater access of cytotoxic chemotherapy (CT) to the tumor. Indeed, for metastatic colorectal cancer, bevacizumab in combination with established CT regimens has efficacy superior to that of CT alone. Despite ～2-month longer progression-free and overall survival times than with CT alone, patients still progress, possibly because of alternative angiogenic "escape" pathways that emerge independent of VEGF-A, or are driven by hypoxic stress on the tumor. Other VEGF family members may contribute to resistance, and many factors that contribute to the regulation of tumor angiogenesis function as part of a complex network, existing in different concentrations and spatiotemporal gradients and producing a wide range of biologic responses. Integrating these concepts into the design and evaluation of new antiangiogenic therapies may help overcome resistance mechanisms and allow for greater efficacy over longer treatment periods.     

MET and VEGF: synergistic targets in castration-resistant prostate cancer

Recent advances in the treatment of prostate cancer have resulted in improved outcomes, including longer survival, but new options are needed for treating patients with castration-resistant disease, particularly in the presence of bone metastasis. Data from preclinical models and clinical biomarker studies indicate that antiangiogenic agents should be a promising treatment for this patient population, and multiple agents in this class have demonstrated activity in early-stage clinical trials. Pivotal trials in prostate cancer with agents targeting vascular endothelial growth factor (VEGF) signalling have resulted in significant improvements in tumour response and progression-free survival. However, overall survival was not significantly improved. Recent preclinical studies suggest that the limited impact on overall survival may result from the development of evasive resistance after inhibition of angiogenesis, possibly through upregulation of MET (hepatocyte growth factor receptor) signalling. MET plays important roles in angiogenesis, tumour cell invasion and bone metastasis, all of which are key factors in castration-resistant prostate cancer. Inhibition of both the MET and VEGF pathways may improve the efficacy of angiogenesis inhibitors in prostate cancer.     

Drug insight: VEGF as a therapeutic target for breast cancer

Angiogenesis is implicated in the pathogenesis of malignancy and metastasis. Inhibition of angiogenesis has demonstrated clinically significant improvements in outcomes in a variety of malignancies, including breast cancer. The humanized monoclonal antibody against VEGF, bevacizumab, is the clinically most mature of the antiangiogenic agents and has recently been shown to improve outcome when combined with chemotherapy in the first-line metastatic setting of breast cancer. A variety of other antiangiogenic agents are currently under investigation, including drugs that inhibit the VEGF receptor 2, the cognate receptor for VEGF found on endothelial cells. The combination of antiangiogenic drugs with one another and with other biologic agents is also being explored in an attempt to improve efficacy and to overcome the drug resistance seen with the initial studies of antiangiogenic agents. This Review will focus on the current state of therapeutics designed to inhibit this angiogenic process in breast cancer.     

Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity

Primary tumors and metastases require blood vessel formation to support their continued growth and eventual metastasis. They use existing vasculature during initial growth but eventually must orchestrate the development and maintenance of new vessels--a process termed angiogenesis--to grow beyond a small size and spread. Angiogenesis is regulated by a number of soluble factors, the relative proportions of which can exacerbate or inhibit the process. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, produced by the majority of human solid tumors. Inhibitors of VEGF might have an impact on the growth and metastasis of these cancers. The relevance of this strategy to the treatment of colorectal cancer was first successfully demonstrated in human clinical trials using a monoclonal antibody against VEGF. A potent antiangiogenic soluble recombinant decoy, VEGF Trap is a protein constructed from VEGF receptor-binding domains linked to an immunoglobulin G(1) constant region. It possesses an affinity for VEGF that is significantly higher than that of the monoclonal antibody. VEGF Trap has demonstrated marked efficacy in halting angiogenesis and shrinking tumors in preclinical animal models and is currently being studied in phase I clinical trials in humans with advanced solid malignancies.     

The potential of antiangiogenic therapy in non-small cell lung cancer.

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.     

Cediranib/AZD2171 inhibits bone and brain metastasis in a preclinical model of advanced prostate cancer

Late stage or aggressive cancers exhibit metastatic growth at multiple sites, and the characterization of treatment response in various organs to drugs with potentially wide-ranging efficacy is needed. Tumor cells that induce angiogenesis are a common characteristic of metastatic disease, and clinically, antiangiogenic therapies have shown value in the setting of advanced cancer. However, recent preclinical studies have suggested that exposure to antiangiogenic drugs can increase tumor invasiveness and metastasis, making it important to determine which contexts antiangiogenic therapy is most appropriate. We describe here the effects of cediranib, a receptor tyrosine kinase inhibitor, in a model of advanced prostate cancer metastatic to skeleton and brain. Treatment with cediranib decreased metastatic tumor burden in the brain and bone, decreased cerebral vasogenic edema, and improved survival, despite increasing the invasive histology of brain metastases. Short-duration cediranib treatment given at the time of tumor cell dissemination was sufficient to inhibit the establishment and subsequent growth of bone metastases, although brain metastases were subject to rebound growth after the discontinuation of cediranib. Distinct growth patterns at different organ sites in the same animal showed that certain tumor microenvironments such as bone may be most amenable to interventions by anti-vascular endothelial growth factor (VEGF) therapies. In addition, anti-VEGF treatment may be of utility in decreasing the rapid growth of solid brain metastases and vasogenic edema in patients with advanced cancer, leading to reduced morbidity and associated clinical benefit.