Angiogenic inhibitors: a new therapeutic strategy in oncology

Angiogenesis is a multistep, complex and tightly regulated process that is necessary for tumor growth and metastasis. Based on data of preclinical models, several antiangiogenic compounds has been shown to modify activated tumor endothelium, which suggests that these compounds can improve cytotoxic drug delivery. Such agents have entered clinical trials as single agents or in combination with cytotoxic drugs, and have shown promising antitumor activity. The pharmacodynamic and pharmacokinetic characteristics of antiangiogenic drugs are reviewed here. Most of the early clinical testing of these agents was conducted in patients with advanced disease resistant to standard therapies. Phase III trials compared the efficacy of standard chemotherapy alone with standard chemotherapy in combination with an experimental angiogenesis inhibitor. Although some of these studies were negative or controversial, recent studies validated in large clinical trials with an anti-vascular endothelial growth factor antibody demonstrated significant clinical benefit and renewed enthusiasm for this therapeutic strategy. This review describes the clinical studies of antiangiogenic agents and highlights the challenges related to choosing appropriate strategies for the selection of patients, study design and choice of appropriate endpoints for the studies' development.     

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.     

Targeting angiogenesis for the treatment of sarcoma

PURPOSE OF REVIEW: More therapeutic options are needed for bone and soft tissue sarcomas, especially for patients with metastatic disease. Recent randomized clinical trials conducted in colon, breast and lung cancer have shown the anti-vascular endothelial growth factor agent, bevacizumab, alone or in combination with chemotherapy, improves response and survival. Preclinical studies have demonstrated the anti-tumor effects of varied anti-angiogenic agents in sarcoma cell lines and tumor models. RECENT FINDINGS: Preclinical studies in sarcomas have evaluated the role of targeted agents including platelet-derived growth factor, matrix metalloproteinases, urokinase receptor and varied small-molecule tyrosine kinase inhibitors. Novel angiogenesis inhibitors are being studied in the treatment of sarcoma, including monoclonal antibodies against vascular endothelial growth factor, cis- and trans-retinoic acids, thalidomide, and tyrosine kinase inhibitors. Phase I, II and III clinical trials continue to evaluate these agents alone, in combinations together and combined with standard chemotherapy. We review herein the preclinical rationale and clinical trial results of anti-angiogenesis therapy in the treatment of soft tissue and bone sarcoma. SUMMARY: Preclinical mechanistic study and clinical trials are continuing in order to evaluate the therapeutic role and ultimately validate the efficacy of the varied anti-angiogenesis agents in soft tissue and bone sarcoma.     

Vascular endothelial growth factor inhibitors in malignant gliomas

Glioblastomas are highly vascularized tumors. Treatment strategies targeting angiogenesis have demonstrated promising results in preclinical studies and clinical trials in patients with malignant gliomas. Anti-VEGF agents, either alone or in combination with chemotherapy, have been associated with reduction in vasogenic brain edema, and prolonged progression-free survival. Larger prospective clinical trials are needed to validate these results, and to assess the impact of these agents on overall survival. Unfortunately, antiangiogenic treatment inevitably fails in most patients. Further studies are needed to understand the molecular pathways that enable a tumor to evade antiangiogenic therapy.     

Design of clinical trials of radiation combined with antiangiogenic therapy

Clinical trials showing longer survival when chemotherapy is combined with antiangiogenic agents (AAs) have led to growing interest in designing combined modality protocols that exploit abnormalities in tumor vasculature. Approved agents include bevacizumab, a recombinant monoclonal antibody that binds to vascular endothelial growth factor, and two small molecule multitargeted tyrosine kinase inhibitors of angiogenesis (SU11248 and BAY-43-9006) that have been approved for therapy of renal cancer. Targeting tumor vasculature has a strong biological rationale in radiation therapy, and preclinical studies consistently show an increase in radiosensitization with combined treatment. Preclinical studies indicate that excessive damage to tumor vasculature can result in radioresistance in some situations, and early clinical data suggest that treatment sequencing may be important when combining AAs with radiation. Radiation itself appears to antagonize any hypoxia that can be induced by long-term administration of AAs. The optimal biological doses of AAs with radiotherapy are unknown, and surrogate markers of efficacy remain to be validated. Early clinical trials should therefore include studies designed to identify mechanisms of interaction and increases in tumor hypoxia. This review highlights preclinical and early clinical data that are relevant for clinical trial design. Optimal radiation planning and delivery is required to minimize the volume of irradiated normal organs and to establish safe dose-volume parameters for phase II-III clinical trials.     

Thérapies ciblées dans le carcinome hépatocellulaire: indications et perspectives

For decades, therapeutic management of advanced-stage hepatocellular carcinoma (HCC) was hampered by marginal and limited benefit of conventional chemotherapy. HCC is a highly vascularised tumor, in which angiogenesis plays a major role in all stages of the disease, and resulted in a rational use of antiangiogenic therapies. Moreover, several tyrosine-kinase receptors have been implicated in the proliferation and invasion of HCC, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Recently, the approval of sorafenib, a multikinase inhibitor, as an efficient therapy for advanced-stage HCC sparked an interest in evaluating new antiangiogenic therapies in the initial and advanced stages of the disease. Currently, several molecules are investigated in preclinical studies and clinical trials with disparate results, with the hope to identify new efficient therapies, thereby opening new prospects and raising several questions and challenges.     

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.     

Progress in antiangiogenic gene therapy of cancer

BACKGROUND: Because tumors require angiogenesis for growth, inhibiting angiogenesis is a promising strategy for treating cancer patients. Although numerous endogenous angiogenesis inhibitors have been discovered, the clinical evaluation of these agents has been hindered by high dose requirements, manufacturing constraints, and relative instability of the corresponding recombinant proteins. Therefore the delivery of these proteins using gene therapy has become increasingly attractive. METHODS: Based on their own antiangiogenic gene therapy research, the authors evaluated the published experience with antiangiogenic gene therapy models using the National Library of Medicine's PubMed search service and the reference lists of the publications cited. RESULTS: Greater than 40 endogenous inhibitors of angiogenesis have been characterized. Thirteen have been employed in gene therapy models, all of which showed antitumor activity in experimental animals. Other approaches have inhibited the expression or activity of proangiogenic cytokines such as vascular endothelial growth factor. The ideal gene delivery vector would target tumor tissue preferentially to minimize systemic toxicity of the transgene product. However, the low toxicity profile of endogenous inhibitors of angiogenesis has allowed the success of systemic antiangiogenic gene therapy in a number of preclinical models, in which normal host tissues act as a "factory" to produce high circulating concentrations of antiangiogenic proteins. CONCLUSIONS: Difficulties with the large-scale use of antiangiogenic agents have hindered their investigation in clinical trials. Antiangiogenic gene therapy offers the potential for cancer patients to manufacture their own antiangiogenic proteins. This strategy has been increasingly successful in preclinical models and represents an exciting new approach to cancer therapy.     

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.     

Evaluating antiangiogenesis agents in the clinic: the Eastern Cooperative Oncology Group Portfolio of Clinical Trials.

Recent evidence indicates that treatment with a humanized monoclonal antibody (bevacizumab) directed at vascular endothelial growth factor improves response and survival in metastatic colorectal cancer when added to standard chemotherapy, validating angiogenesis as a therapeutic target. Investigators from the Eastern Cooperative Oncology Group (ECOG) have initiated a number of Phase III studies that will help further define the role of antiangiogenic agents for the treatment of breast, colon, lung, renal, and head and neck cancer, as well as melanoma and myeloma. The agents being evaluated target various biological functions involved in angiogenesis, including vascular endothelial growth factor (bevacizumab), endothelial cell proliferation (thalidomide, IFN-alpha), and matrix metalloproteinases (marimastat). These clinical trials include correlative laboratory studies aimed at elucidating how these agents may exert their clinical effects. The portfolio of Eastern Cooperative Oncology Group studies will serve to further define the role of this therapeutic strategy for patients with advanced cancer.     

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.     

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.     

Preclinical data targeting vascular endothelial growth factor in colorectal cancer

Vascular endothelial growth factor (VEGF) is the driving force behind angiogenesis in most solid malignancies. This also holds true for colorectal cancer (CRC), where increased levels of VEGF in primary cancers are associated with increased microvessel density and poor prognosis. These findings have led to preclinical studies evaluating the efficacy of anti-VEGF therapy in inhibiting the growth of CRC in ectopic and orthotopic locations. In preclinical models, numerous approaches to inhibit VEGF activity led to decreased tumor growth and angiogenesis. These studies led to clinical trials in which, unfortunately, single-agent anti-VEGF therapy was relatively ineffective for patients with metastatic CRC. However, combinations of anti-VEGF therapies with chemotherapy have clearly demonstrated clinical benefit. Understanding the mechanisms of the role of VEGF in CRC angiogenesis and the effect of anti-VEGF therapy on the tumor vasculature will allow oncologists to optimize therapeutic regimens targeting VEGF and its receptors.     

Angiogenesis and hepatic colorectal metastases

Angiogenesis is a critical step in the metastatic cascade of colorectal cancer. Several angiogenesis inhibitors have been evaluated in animal models and have shown efficacy, but challenges remain in using these drugs effectively in the clinical setting. Although several of these angiogenesis inhibitors are currently being evaluated in clinical trials, alone or in combination with cytotoxic chemotherapy, early results suggest that angiogenesis inhibitors alone, when used for advanced disease, have minimal activity. It is likely that this class of drugs will prove more efficacious when used either in the setting of minimal disease as agents that may promote tumor dormancy or in combination with other conventional forms of therapy. In addition, strategies such as metronomic therapy have been proposed whereby lower doses of cytotoxic chemotherapy, given more frequently, may act via an antiangiogenic mechanism [67,68]. Another challenge is identifying methods of assessing response to antiangiogenic therapy. To date, traditional methods of identifying response to treatment have not proven effective. Several investigators are working toward identifying circulating endothelial or tumor-associated factors that may be useful in following treatment. Novel imaging techniques are also being evaluated with enhanced CT and MRI, and newer modalities. Hepatic colorectal metastases provide an opportune setting in which to accomplish these challenges because the high incidence of disease and the ability to measure tumor with a variety of techniques lend themselves to evaluation of antiangiogenic therapy.     

Antiangiogenic therapy for ovarian cancer

PURPOSE OF REVIEW: To highlight the current antiangiogenic compounds being evaluated as single agents or in association with chemotherapy in the treatment of ovarian cancer, as well as the rationale for their development. RECENT FINDINGS: Several proangiogenic factors may be potential targets for antiangiogenic therapy in ovarian cancer. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been evaluated as a single agent in two phase II clinical trials and in combination with chemotherapy in three phase II studies, with promising results. This agent is also being evaluated in association with chemotherapy in two phase III clinical trials, both in the treatment and in the maintenance settings. Heparanase inhibitors and inhibitors of platelet-derived growth factor signalling remain as potential agents to be investigated in phase II trials. The development of biomarkers to define appropriate dosing regimens and predict which patients may benefit from antiangiogenic therapies is of great importance. SUMMARY: Data from preclinical and clinical studies reported in the last 2 years demonstrate the importance of several proangiogenic factors in the prognosis of ovarian cancer, suggesting possible new targets for antiangiogenic therapy. The agents that are currently being investigated in phase II and III clinical trials include bevacizumab, erlotinib, sunitinib, sorafenib and vascular endothelial growth factor Trap, and the results of these trials will have significant implications in the future management of ovarian cancer.     

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.     

Current status and perspective of antiangiogenic therapy for cancer: urinary cancer

Angiogenesis is considered a prerequisite for solid tumor growth. Antiangiogenic therapy reduces tumor size and extends host survival in a number of preclinical animal models. However, in humans antiangiogenic therapy is a poor promoter of tumor regression and has shown minimal effect on patient survival. In urinary cancers, such as renal cell cancer, prostate cancer, and bladder cancer, advanced refractory disease is a good candidate for antiangiogenic therapy because of its resistance to ordinary chemotherapy, radiotherapy, and hormonal therapy. Unique characteristics of molecular mechanisms underlie the induction of angiogenesis in urinary cancers. In this review, we summarize these unique mechanisms and review the results of clinical trials of antiangiogenic therapy for these cancers, discussing prospects and problems relating to antiangiogenic therapy.     

Targeted therapy in rectal cancer

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. Based on successful randomized phase III trials, anti-EGFR and anti-VEGF therapeutics have entered clinical practice. Cetuximab (Erbitux), an EGFR-specific antibody, is currently approved in the United States in combination with irinotecan (Camptosar) for patients with metastatic colorectal cancer refractory to irinotecan or as a single agent for patients unable to tolerate irinotecan-based therapy. In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly inferior disease-free survival and lower rates of achieving pathologic complete response. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine cetuximab with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Bevacizumab (Avastin), a VEGF-specific antibody, was the first antiangiogenic agent to be approved in the United States for use in combination with standard chemotherapy in the first- and second-line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels, and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also "normalize" tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. This review will address completed and ongoing trials that have established and continue to clarify the effects of these agents in rectal cancer.     

Prospects for therapeutic inhibition of neuroblastoma angiogenesis

Despite aggressive therapy, survival for advanced stage neuroblastoma remains poor with significant long-term morbidity in disease survivors. High-risk disease features are strongly correlated with tumor vascularity, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. However, challenges include the well-known clinical heterogeneity and embryonal origins of this disease, which suggests a complex regulation of neovascularization that may be distinct from epithelial-derived carcinomas. We will review what is understood about angiogenesis-related signaling in neuroblastoma. In particular, we will present evidence that angiogenesis-related molecules are differentially expressed in primary neuroblastomas in a pattern suggesting promotion of a pro-angiogenic phenotype in high-risk tumors and an anti-angiogenic phenotype in low-risk tumors. We will also discuss a variety of vascular inhibition strategies that have been used in neuroblastoma preclinical models including specific inhibition of vascular endothelial growth factor (VEGF) and methionine aminopeptidase 2 (MetAP2). Recent observations that the combination of angiogenesis inhibitors with conventional chemotherapy provides synergy without additive toxicity, suggests the potential use of angiogenesis inhibitors as an adjunct between cycles of conventional cytotoxic therapy. Further identification of critical angiogenic signaling pathways and evaluation of specific inhibitors in preclinical neuroblastoma models should provide justification for future selection and evaluation of angiogenesis inhibitors in clinical trials for high-risk neuroblastoma patients.     

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.