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.     

A systems approach to cancer therapy

Conclusion The molecules described herein as antiangiogenic agents and antimetastatic agents represent a wide variety of molecular structures with a wide variety of biological effects and targets. Most often these agents have been generally classified as antiangiogenic or antimetastatic by their effects in an in vitro bio-assay system. The diversity in this group of molecules gives strength to the potential of this approach in therapeutic applications. The biological and biochemical pathways involved in angiogenesis are numerous and redundant. It is likely that there are many angiogenic factors and many pathways of invasion, therefore it is likely that blockade of more than one pathway related to angiogenesis and/or invasion will be necessary to impact on the natural progress of a malignant disease.The vasculature forms the first barrier to penetration of molecules into tumors. Although the antiangiogenic agent treatments administered in this study did not inhibit angiogenesis in these tumors completely, the vasculature present in the treated tumors may be impaired compared to control tumors. Overall, therefore, the best speculation is that the main targets for the antiangiogenic agents are extracellular matrix processes and/or tumor endothelial cells and that inhibition and/or impairment of these non-malignant functions can improve therapeutic responses when used in combination with cytotoxic therapies. The incorporation of antiangiogenic agents and/or antimetastatic agents into therapeutic regimens represents an important challenge. The successful treatment of cancer requires the eradication of all malignant cells and therefore treatment with cytotoxic therapies. The compatibility of antiangiogenic therapy and/or anti-invasion agents with cytotoxic chemotherapeutic agents is not obvious [316].The goal of the addition of any non-cytotoxic potentiator to a therapeutic regimen is to take a good therapy and, without additional toxicity, push it to cure.Cyclophosphamide is a good drug against the Lewis lung carcinoma although no long-term survivors of animals bearing Lewis lung carcinoma are achieved with cyclophosphamide treatment alone. Adding antiangiogenic agents to treatment of this tumor with cyclophosphamide produced a cure rate of 40–50%, meaning that both the primary and metastatic disease has been eradicated in these animals. Cures were achieved only when the antiangiogenic treatments extended from days 4–18 post Lewis lung tumor implantation. The results obtained with the addition of antiangiogenic agents to cytotoxic anticancer therapies in in vivo models of established solid tumors have been very positive and provide direction for future clinical trials including these antiangiogenic agents. Two conclusions may be drawn. First, combinations of antiangiogenic and/or antimetastatic agents evoke a greater effect on tumor response to therapy than does treatment with single agents of these classes. Second, treatment with antiangiogenic agents and/or antimetastatic agents can interact in a positive way with cytotoxic therapies.     

Antiangiogenics and immunotherapies in cervical cancer: an update and future’s view

Despite availability of primary and secondary prevention measures, cervical cancer (CC) persists as one of the most common cancers among women around the world, and more than 70% of cases are diagnosed at advanced stages. Although significant progress has been made in the treatment of CC, around 15–61% of patients develop a recurrence in lymph nodes or distant sites within the first 2 years of completing treatment and the prognosis for these patients remains poor. During the last decades, in an attempt to improve the outcome in these patients, novel agents as combination therapy that target known dysfunctional molecular pathways have been developed with the most attention to the inhibitors of the angiogenesis process. One therapeutic target is the vascular endothelial growth factor, which has been shown to play a key role in tumor angiogenesis, not only for growth of new tissue but also in tumor proliferation. Bevacizumab is recognized as a potent antiangiogenic agent in ovarian cancer but has also demonstrated encouraging antitumor activity in recurrent CC. Moreover, other antiangiogenic agents were recently under study including: sunitinib, sorafenib, pazopanib, cediranib and nintedanib with interesting preliminary results. Moreover, over the last few years there has been increasing interest in cellular immunotherapy as a strategy to harness the immune system to fight tumors. This article focuses on recent discoveries about antiangiogenic agents and immunotherapies in the treatment of CC highlighting on future’s view.     

Antiangiogenic Chemotherapeutic Agents

The mechanism of action of anticancer chemotherapeutic agents is mainly thought to be due to a direct inhibition of tumor cell proliferation. The enhanced endothelial cell proliferation rate in tumor specimens raised the question whether therapeutic effects of chemotherapeutic agents might be at least partially attributed to an inhibition of tumor angiogenesis. Meanwhile, numerous anticancer chemotherapeutic agents were tested for their antiangiogenic potential. A few agents seem to exert consistent inhibition of tumor angiogenesis even in drug-resistant tumors. Most recent investigations on the antiangiogenic efficacy of different application schedules suggested the use of a tightly spaced, continuous application of appropriate anticancer chemotherapeutic agents. These application schedules are able to exert a strong antiangiogenic effect as indicated by an increase of apoptosis of tumor endothelial cells. Future clinical trials have to determine the therapeutic benefit of novel combination chemotherapy and alternative application schedules.     

Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions.

Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth factor antibody combined with chemotherapy as front-line therapy of metastatic colorectal cancer have renewed enthusiasm for this therapeutic strategy. This article presents an overview of experimental and clinical studies of combined therapy with antiangiogenic agents and highlights the challenges related to the appropriate strategies for selection of the patients, study design, and choice of proper end points for preclinical and clinical studies using these agents.     

Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction.

Recent preclinical studies have suggested that radiotherapy in combination with antiangiogenic/vasculature targeting agents enhances the therapeutic ratio of ionizing radiation alone. Because radiotherapy is one of the most widely used treatments for cancer, it is important to understand how best to use these two modalities to aid in the design of rational patient protocols. The mechanisms of interaction between antiangiogenic/vasculature targeting agents and ionizing radiation are complex and involve interactions between the tumor stroma and vasculature and the tumor cells themselves. Vascular targeting agents are aimed specifically at the existing tumor vasculature. Antiangiogenic agents target angiogenesis or the new growth of tumor vessels. These agents can decrease overall tumor resistance to radiation by affecting both tumor cells and tumor vasculature, thereby breaking the codependent cycle of tumor growth and angiogenesis. The hypoxic microenvironment of the tumor also contributes to the mechanisms of interactions between antiangiogenic/vasculature targeting agents and ionizing radiation. Hypoxia stimulates up-regulation of angiogenic and tumor cell survival factors, giving rise to tumor proliferation, radioresistance, and angiogenesis. Preclinical evidence suggests that antiangiogenic agents reduce tumor hypoxia and provides a rationale for combining these agents with ionizing radiation. Optimal scheduling of combined treatment with these agents and ionizing radiation will ultimately depend on understanding how tumor oxygenation changes as tumors regress and regrow during exposure to these agents. This review article explores the complex interactions between antiangiogenic/vasculature targeting agents and radiation and offers insight into the mechanisms of interaction that may be responsible for improved tumor response to radiation.     

Tumor progression-dependent angiogenesis in gastric cancer and its potential application

Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.     

Vascular Targeting and Therapeutics for Squamous Cell Carcinoma of the Head and Neck

Close to 38 500 new cases of squamous cell carcinoma of the head and neck (SCCHN) are diagnosed each year. Traditional therapy for SCCHN has involved a multimodality approach of radiotherapy, surgery, and chemotherapy. More recently, novel therapeutic targets for solid tumors, including SCCHN, have been subject to preclinical and clinical applications. One of these newer approaches is antiangiogenic therapy. The mechanism of angiogenesis and the role it plays in tumor growth has been the subject of extensive investigation over the last 3 decades. As new antiangiogenic agents are being approved for the treatment of various solid tumors this critical review, using current preclinical and clinical evidence available thus far, examines the possible future role this new modality will have in the management of SCCHN. The different steps of angiogenesis and the corresponding targets are discussed, with a focus on vascular endothelial growth factor, as well as the preclinical and clinical evidence for the role of angiogenesis in SCCHN.     

Antiangiogenic therapies in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and lethal of adult gliomas. The prognosis for the great majority of patients with GBM is poor as almost all tumors recur following optimal surgical resection, radiation and standard chemotherapy, resulting in rapid disease-related death. The standard of care for recurrent GBM has not been clearly established. GBMs are highly vascularized brain tumors and growth has been shown to be angiogenesis dependent, thus stimulating interest in developing antiangiogenic therapeutic strategies. Antiangiogenic agents are the most promising novel agents in development for GBM but to date have not substantially changed overall survival. Future antiangiogenic strategies designed to overcome limitations of current antiangiogenic agents will likely involve the use of agent combinations that target pathways mediating resistance to antiangiogenic agents and tumor invasion.     

Inhibition of angiogenesis and invasion in malignant gliomas

Malignant gliomas confer a dismal prognosis. As the molecular events that underlie tumor angiogenesis are elucidated, angiogenesis inhibition is emerging as a promising therapy for recurrent and newly diagnosed tumors. Data from animal studies suggest that angiogenesis inhibition may promote an invasive phenotype in tumor cells. This may represent an important mechanism of resistance to antiangiogenic therapies. Recent studies have begun to clarify the mechanisms by which glioma cells detach from the tumor mass, remodel the extracellular matrix and infiltrate normal brain. An array of potential therapeutic targets exists. Combination therapy with antiangiogenic and novel anti-invasion agents is a promising approach that may produce a synergistic antitumor effect and a survival benefit for patients with these devastating tumors.     

Inhibition of angiogenesis and invasion in malignant gliomas

Malignant gliomas confer a dismal prognosis. As the molecular events that underlie tumor angiogenesis are elucidated, angiogenesis inhibition is emerging as a promising therapy for recurrent and newly diagnosed tumors. Data from animal studies suggest that angiogenesis inhibition may promote an invasive phenotype in tumor cells. This may represent an important mechanism of resistance to antiangiogenic therapies. Recent studies have begun to clarify the mechanisms by which glioma cells detach from the tumor mass, remodel the extracellular matrix and infiltrate normal brain. An array of potential therapeutic targets exists. Combination therapy with antiangiogenic and novel anti-invasion agents is a promising approach that may produce a synergistic antitumor effect and a survival benefit for patients with these devastating tumors.     

The interaction of radiation therapy and antiangiogenic therapy

Since its beginning in the early 1970s, the field of angiogenesis research has grown rapidly and it has now become apparent that the endothelial cell is a critical regulator of the malignant phenotype. Multiple antiangiogenic agents have now been used in the clinic yet a better understanding of the process of angiogenesis is still needed before these agents can be successfully incorporated into clinical practice. Although antiangiogenic agents offer great therapeutic potential, preclinical and clinical studies suggest that these agents will have a delayed onset of activity and may only induce disease stabilization for patients with advanced malignancy. The use of radiation therapy for cancer is also associated with therapeutic challenges that are distinct from those that might be expected with antiangiogenic agents. Thus, the use of angiogenesis inhibitors in combination with radiation therapy should help to overcome the limitations of each leading to enhanced efficacy and diminished toxicity. The goal of this review is to provide an update of ongoing progress and current challenges related to the use of angiogenesis inhibitors with radiation therapy.     

Antiangiogenic therapy in the management of breast cancer

An improved understanding of the important role of angiogenesis in tumor biology has led to development of different antiangiogenic therapies. Numerous clinical studies for several antiangiogenic agents have recently been conducted in breast cancer patients and have shown clinically significant improvement in outcomes. This review focuses on current progress in the field of antiangiogenic therapy in the management of breast cancer, also highlighting issues regarding future therapeutic development that result in the greatest clinical benefits and minimizing the adverse effects.     

Current status and perspective of antiangiogenic therapy for cancer: hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is well known as a typical angiogenic tumor, especially in the moderately to poorly differentiated type. Such clinicopathological characteristics are not only useful for imaging diagnosis but are also applicable to the treatment of HCC. In addition, recent molecular studies have revealed that angiogenesis is closely related to hepatocarcinogenesis. In this review, the molecular mechanism of HCC angiogenesis and the antiangiogenic prevention of HCC are reviewed to introduce the latest trends in antiangiogenic treatment of cancers, including HCC.     

Thalidomide and analogues: current proposed mechanisms and therapeutic usage

Microvessel density is a prognostic factor for many cancers, including prostate. For this reason, several studies and therapeutic approaches that target the tumor microvasculature have been attempted. Thalidomide has long been recognized as an antiangiogenic molecule. Recently, this drug has regained favor as an anticancer agent and is in clinical trial for multiple myeloma and prostate cancer, among others. This article will briefly review the proposed mechanisms of action for thalidomide, discuss why these activities are of therapeutic value in diseases currently undergoing clinical trials, and summarize the current status of clinical trials for prostate cancer. The focus will be predominantly on the relationship of thalidomide to angiogenesis, as well as on the future and potential value of thalidomide-inspired structural derivatives.     

The combination of antiangiogenic therapy with other modalities

Angiogenesis is critical for a number of physiologic and pathophysiologic processes, and several angiogenesis inhibitors are now in clinical trials for the treatment of cancer. Antiangiogenic therapy offers a number of potential benefits including lack of drug resistance for some agents, synergistic interaction with other modalities, lack of significant toxicity compared with conventional agents, and a potent antitumor effect. However, no angiogenesis inhibitor has been approved for clinical use. Although antiangiogenic agents offer great therapeutic potential, preclinical and early clinical trial results suggest that these agents will have a delayed onset of activity and may induce stabilization of disease, and not regression, in patients with advanced disease. Studies suggest that regulation of angiogenesis in various capillary beds may be differentially regulated, suggesting that antiangiogenic therapy may require organ-specific optimization. By combining antiangiogenic agents with each other and/or with other modalities used in the treatment of cancer, the limitations of each therapeutic approach will be overcome, leading to enhanced efficacy with diminished toxicity. However, the optimal strategies forthe use, monitoring, and validation of antiangiogenic agents in the clinic remains unclear. Before these agents can be integrated into clinical practice, a better understanding of their mechanism of action and regulation is     

Biological and clinical role of angiogenesis in breast cancer

Summary Angiogenesis, the process leading to the formation of new blood vessels, plays a central role in tumor progression of solid neoplasia. The switch from the avascular to the vascular phase is generally accompanied by rapid primary tumor growth and local invasiveness. Furthermore, angiogenesis is also necessary both at the beginning and at the end of the development of distant metastasis and is implicated in the phenomenon of dormant micrometastases.The angiogenic activity of both the primary tumor and its metastases is the result of the net balance between angiogenic peptides and natural inhibitors, and it is regulated by multiple biochemical and genetic mechanisms. In normal tissues of the adult, unlike invasive cancers, the angiogenic inhibitory pathway predominates.Several experimental and clinico-pathologic studies have confirmed that angiogenesis is specifically involved in transformation and progression of human breast cancer. In particular, clinicopathologic studies have found that the degree of vascularization of primary invasive human breast cancer is heterogeneous and correlates with the prognosis of patients.A number of antiangiogenic agents have been recently discovered, and some are under early clinical evaluation. Thus, angiogenic activity of the tumors represents a potentially novel anticancer therapeutic target.This issue ofBreast Cancer Research and Treatment reports on the most relevant basic biological aspects of angiogenesis, on its clinical role in breast cancer prognosis, and on the implications of inhibition of angiogenesis for future novel anticancer therapeutic approaches.     

Broad-spectrum G protein-coupled receptor antagonist, [D-Arg1,D-Trp5,7,9,Leu11]SP: a dual inhibitor of growth and angiogenesis in pancreatic cancer

Substance P analogues, including [D-Arg(1),D-Trp(5,7,9),Leu(11)]SP (SPA) are broad-spectrum G protein-coupled receptor (GPCR) antagonists that have potential antitumorigenic activities, although the mechanism(s) are not completely understood. Here, we examined the effects of SPA in ductal pancreatic cancers that express multiple GPCRs for mitogenic agonists and also produce proangiogenic chemokines. Using HPAF-II, a well-differentiated pancreatic cancer cell line as our model system, we showed that SPA inhibited multiple neuropeptide-induced Ca(2+) mobilization, DNA synthesis, and anchorage-independent growth in vitro. SPA also significantly attenuated the growth of HPAF-II tumor xenografts in nude mice beyond the treatment period. Interestingly, SPA markedly increased apoptosis but moderately decreased proliferation marker, Ki-67 in the tumor xenografts implying additional mechanism(s) for the significant growth inhibitory effect observed in vivo. HPAF-II cells express ELR(+) CXC chemokines, including IL-8/CXCL8, which bind to CXCR2 (a member of GPCR superfamily) and promote angiogenesis in multiple cancers, including pancreatic cancer. SPA inhibited CXCR2-mediated Ca(2+) mobilization and blocked specifically IL-8/CXCL8-induced angiogenesis in rat corneal micropocket assay in vivo. A salient feature of the results presented here is that SPA markedly reduced tumor-associated angiogenesis in the HPAF-II xenografts in vivo. Our results show that SPA, a broad-spectrum GPCR antagonist attenuates tumor growth in pancreatic cancer via a dual mechanism involving both the antiproliferative and antiangiogenic properties. We conclude that this novel dual-inhibitory property of SPA could be of significant therapeutic value in pancreatic cancer, when used in combination with other antiproliferative and/or antiangiogenic agents.     

Angiogenesis as a Therapeutic Target in Malignant Gliomas

Currently, adult glioblastoma (GBM) patients have poor outcomes with conventional cytotoxic treatments. Because GBMs are highly angiogenic tumors, inhibitors that target tumor vasculature are considered promising therapeutic agents in these patients. Encouraging efficacy and tolerability in preliminary clinical trials suggest that targeting angiogenesis may be an effective therapeutic strategy in GBM patients. However, the survival benefits observed to date in uncontrolled trials of antiangiogenic agents have been modest, and several obstacles have limited their effectiveness. This article reviews the rationale for antiangiogenic agents in GBM, their potential mechanisms of action, and their clinical development in GBM patients. Although challenges remain with this approach, ongoing studies may improve upon the promising initial benefits already observed in GBM patients.     

Inhibition of Angiogenesis for the Treatment of Metastatic Melanoma

Metastatic malignant melanoma is a uniformly fatal disease. Tumor growth and metastasis are associated with angiogenesis and lymphangiogenesis. Proangiogenic factors are associated with higher disease burdens and worse outcomes in melanoma. Accordingly, many agents that target angiogenesis have been studied in melanoma. Angiogenesis is a complex, multifaceted process with many potential therapeutic targets. So far, monoclonal antibodies, immune conjugates, tyrosine kinase inhibitors, immunomodulatory agents, and other therapies have been tested in the phase 2 or phase 3 setting for the treatment of metastatic melanoma. The antiangiogenic agents that have been tested to date offer little activity as single agents, but in combination with cytotoxic agents prolong progression-free survival. We explore data from published phase 2 and phase 3 trials in addition to the purported mechanisms of action of antiangiogenic agents.