Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.

New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.     

Vascular endothelial growth factor as a target for anticancer therapy

The development of a vascular supply is a critical factor in the growth and metastatic spread of malignant tumors. Of the multitude of growth factors that regulate physiological and pathological angiogenesis, vascular endothelial growth factor (VEGF) is believed to be the most important. There is evidence that overexpression of VEGF is correlated with an adverse prognosis, at least in some tumors. Tumor-expressed VEGF is particularly attractive as a target for anticancer therapy because its angiogenesis-promoting activity is at the level of the endothelial cell and, compared with agents that directly target tumor cells, tumor penetration is less critical for VEGF inhibitors. Moreover, recent work has shown that inhibiting tumor angiogenesis increases the effectiveness of coadministered chemotherapy and radiotherapy. This suggests that drugs that target VEGF or its receptors can be combined with traditional treatment modalities to ensure maximum effectiveness. A variety of agents aimed at blocking VEGF or its receptor-signaling system are currently being developed for the treatment of cancer. Of these, bevacizumab, a humanized monoclonal antibody directed at VEGF, is the most advanced in clinical development and has shown promising results in clinical trials.     

Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

Angiogenesis is essential for cancer growth and progression. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The addition of bevacizumab, an antibody to vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improves survival compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are a new class of drugs that target the TK domain of the VEGF receptors. To evaluate the role of this class of agents in the treatment of NSCLC, some phase II and phase III studies using these agents alone or in combination with other agents have been completed. This review summarizes the currently available data on VEGFR TKIs in the treatment of NSCLC.     

Tumoral angiogenesis and breast cancer

Breast cancer (BC) is the most common neoplasm in women in Western countries. Tumoral angiogenesis (TA) is essential for the growth and spread of BC cells. There are at least 6 different angiogenic growth factors associated with TA in BC. The major mediator of TA is vascular endothelial growth factor (VEGF), a homodimeric heparin-binding glycoprotein. VEGF signals through VEGF receptor-2 (VEGFR-2), the major VEGF signalling receptor that mediates sprouting angiogenesis. Recently, different antiangiogenic agents have shown efficacy in the treatment of advanced BC. Bevacizumab, a humanised monoclonal antibody against VEGF, in combination with taxanes improves progression-free survival and overall response rate in first-line therapy. Other new antiangiogenic agents, called multi-kinase inhibitors (sunitinib and pazopanib), are under investigation. Finally, a schedule of treatment called metronomic chemotherapy, with antiangiogenic activity, has also demonstrated efficacy in the treatment of advanced BC.     

The role of antiangiogenesis therapy: Bevacizumab and beyond

The importance of angiogenesis in tumour growth and development is well known. Overexpression of vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, is associated with poor prognosis in cancer. As a result, several therapeutic agents that inhibit the actions of VEGF or its receptors are currently in development for use in advanced solid tumours, such breast, colorectal, lung and renal cancer. Clinical data from trials of anti-VEGF agents in this group of tumours are discussed, with a particular focus on the efficacy and safety of bevacizumab, the anti-VEGF agent at the most advanced stage of development in those tumour types. Future potential uses of bevacizumab in cancer therapy will be discussed. Presented in part as a Plenary Lecture at the XXV Anniversary of the Spanish Society for Cancer Research (ASEICA), Santiago de Compostela, 10 July 2008     

Continuum of care with anti-angiogenic therapies in metastatic colorectal cancer

Inhibition of tumor angiogenesis has emerged as an important therapeutic component in the management of metastatic colorectal cancer. Three anti-angiogenic agents are currently approved in this clinical setting: bevacizumab, ziv-aflibercept, and regorafenib. Bevacizumab, a monoclonal antibody that targets the angiogenesis-driving ligand vascular endothelial growth factor A (VEGF-A), is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer, where it can be used in combination with intravenous 5-fluorouracil-containing chemotherapy regimens. In conjunction with second-line chemotherapies, bevacizumab also has anti-cancer activity, both for the management of metastatic colorectal cancer in patients who received it as a part of their first line therapy and for those who are naïve to it. Ziv-aflibercept also has demonstrated clinical activity in conjunction with the chemotherapeutic regimen FOLFIRI in the second line management of patients with metastatic colorectal cancer; it functions by binding VEGF-A to the vascular endothelial growth factor proteins VEGF-B and PIGF (placental growth factor). Regorafenib, which inhibits multiple tyrosine kinases, including the VEGF receptors, has proven clinical benefit in the management of patients with metastatic colorectal cancer refractory to all other therapies. For patients’ whose cancers are refractory to all other therapies, there is also evidence for the use of bevacizumab with fluoropyrimidine monotherapy, but only in the bevacizumab-naïve patient subset. Presently, it is not clear if any one agent as more activity in a particular line of therapy than another, has greater efficacy when paired with a particular chemotherapy backbone, or if a particular patient subset is more likely to benefit from these agents. Given the present benefit and tolerance data, an anti-angiogenic agent should be considered in all lines of therapy in the management of metastatic colorectal cancer, with the evidence for the use of these agents in each specific line of therapy and in specific chemotherapeutic combinations driving agent selection.Key Words: Colorectal cancer, metastatic, angiogenesis, bevacizumab, ziv-aflibercept, regorafenib     

Bevacizumab in the treatment of non-small-cell lung cancer

Lung cancer is the leading cause of cancer death in the United States. The majority of patients present with advanced disease, and treatment with standard cytotoxic chemotherapy improves survival and quality of life in patients with a preserved functional status. However, the prognosis is poor with the majority of patients dying in less than a year. Treatment with standard cytotoxic chemotherapy has reached a therapeutic plateau, and new therapeutic approaches have investigated therapies that target the specific molecular pathways involved in carcinogenesis and angiogenesis. The most promising strategy for inhibiting angiogenesis involves agents that either target the proangiogenesis growth factor, vascular endothelial growth factor A (VEGF) by preventing binding to the receptor or inhibiting the downstream signaling of the vascular endothelial growth factor receptor. The only therapeutic agent approved for the treatment of lung cancer is bevacizumab, a monoclonal antibody that binds to VEGF. A recent phase III trial revealed a statistically significant improvement in response rate, progression free and overall survival with combination of bevacizumab with chemotherapy over chemotherapy alone. Attempts to identify surrogate markers of antiangiogenesis activity are currently ongoing, and may assist in the selection of patients for antiangiogenesis therapy and the development of this class of agents.     

Vascular Endothelial Growth Factor Polymorphisms: Role in Response and Toxicity of Tyrosine Kinase Inhibitors

Angiogenesis is central to the growth of normal tissues and tumors. Inhibiting this pathway has been a strategy for drug development for tumors not responsive to most agents used in chemotherapy. Notably, signaling mediated by vascular endothelial growth factor (VEGF) is a key target because aberrant signaling via this pathway is frequently associated with neoangiogenesis in tumors. The drug-discovery effort to blunt VEGF signaling has led to the approval of bevacizumab and several receptor tyrosine kinase inhibitors (TKIs) that have shown efficacy in the clinical management of breast, colorectal, lung, and kidney cancer. Understanding the genetic variability in VEGF and VEGF receptor has led to identifying genotypic variations (single nucleotide polymorphisms [SNPs]) associated with treatment outcome and toxicity. Notably, identification of SNPs in VEGF associated with angiogenesis inhibitor treatment-induced hypertension and outcome provides exciting opportunities for personalized medicine to improve outcome and reduced toxicity with these novel TKIs.     

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.     

晚期结直肠癌分子靶向治疗

晚期结直肠癌靶向治疗药物主要包括血管内皮生长因子抑制剂和表皮生长因子受体抑制剂.研究表明贝伐珠单抗和西妥昔单抗改善了晚期结直肠癌的预后,但在联合化疗药物方案的选择上稍有差异.西妥昔单抗和贝伐珠单抗改善K-ras野生型晚期结直肠癌患者总生存期相似.新的靶向药物阿柏西普、瑞格非尼等的出现,为晚期结直肠癌的靶向治疗提供了更多的选择.     

Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors.

BACKGROUND: Angiogenesis plays an important role in tumor growth and metastasis. METHODS: We review the function of the vascular endothelial growth factor (VEGF) in vessel formation that is complemented by platelet-derived growth factor (PDGF). We also review the agents designed to target VEGF, PDGF, and/or their receptors. RESULTS: VEGF plays a central role in tumor angiogenesis. It is expressed at increased levels in colorectal, liver, lung, thyroid, breast, as well as in bladder, ovary, uterine cancers, and in angiosarcomas, germ cell tumors, intracranial tumors, and others. VEGF blockade has been shown to have a direct and rapid antivascular effect in both animal and human tumors, through deprivation of tumor vascular supply and inhibition of endothelial proliferation. Overexpression of PDGFs and their receptors has also been reported in many types of cancers such as prostate, ovarian, and non-small-cell lung cancer. Many VEGF and PDGF inhibitors are available. The use of some of these inhibitors has significantly improved the survival of cancer patients. Several agents are in development and currently are being tested in clinical trials. CONCLUSIONS: Angiogenic agents inhibiting VEGF and PDGF have shown promising clinical results. Targeting more than one pathway by combining different agents may increase the antitumor activity of these drugs. The implementation of reliable radiologic and pathologic angiogenesis monitoring techniques is necessary to implement antiangiogenic therapies in cancer.     

Integration of novel agents in the treatment of colorectal cancer

Two of the most promising new targets in the treatment of colorectal cancer are the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Agents that inhibit the EGFR or bind to VEGF have demonstrated clinical activity as single agents and in combination with chemotherapy in phase II and phase III clinical trials. The most promising of these agents are cetuximab, which blocks the binding of EGF and transforming growth factor alpha (TGF-alpha) to EGFR, and bevacizumab, which binds free VEGF. Cetuximab and irinotecan have been evaluated in two clinical studies in the USA (IMCL CP02-0141 and IMCL CP02-9923). Study IMCL CP02-0141 evaluated the antitumor activity of single-agent cetuximab in patients with irinotecan-refractory, EGFR-positive metastatic colorectal carcinoma. There were 6 partial responses in 57 treated patients, for a response rate of 10.5%. Study IMCL CP02-9923 evaluated the combination of cetuximab and irinotecan in a total of 139 patients enrolled at 27 study sites. In this trial 22.5% of patients with progressive disease on irinotecan achieved an objective response (19% by investigator assessment) showing that the combination of cetuximab and irinotecan has antitumor activity in this population. A large randomized phase II trial evaluating similar study populations in Europe confirmed these findings, demonstrating response rates for cetuximab/irinotecan and cetuximab alone of 22.9% and 10.8%, respectively. The other promising agent bevacizumab is a humanized variant of the anti-VEGF monoclonal antibody. VEGF is produced by healthy and neoplastic cells. Its activities are mediated by two receptor tyrosine kinases. VEGF signaling is often a rate-limiting step in physiologic and pathologic angiogenesis. Bevacizumab has been studied as an antiangiogenic cancer therapeutic as a single agent and in combination with chemotherapy in patients with stage III and IV colon cancer. In addition to its direct antiangiogenic effects, bevacizumab may allow more efficient delivery of chemotherapy by altering tumor vasculature and decreasing the elevated interstitial pressure common in tumors. In this regard, some of the most robust phase II data using bevacizumab are from a randomized study of chemotherapy [fluorouracil (5-FU) and leucovorin (LV)] with or without bevacizumab in metastatic colorectal cancer. In this study, treatment with bevacizumab plus 5-FU/LV resulted in higher response rates, longer median time to disease progression, and longer median survival. Recently, a phase III, multicenter, double-blind, randomized, placebo-controlled trial was designed to investigate the addition of bevacizumab to first-line irinotecan, 5-FU, and LV chemotherapy (IFL). The trial showed a higher response rate, longer time to tumor progression, and prolonged overall survival in patients with metastatic colorectal cancer. It was the first large, randomized, phase III survival trial to assess the importance of targeting VEGF and tumor angiogenesis for the treatment of human cancer. Integration of novel agents targeting VEGF and EGFR with irinotecan-based chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. The goal in the future will be to predict which specific chemotherapy and targeted agent combination will most likely benefit individual patients.     

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.     

Anti-VEGF therapy: a new approach to colorectal cancer therapy

The purpose of this review is to discuss the inhibition of vascular endothelial growth factor as a treatment for advanced colorectal cancer. The review will begin by summarizing the theory behind vascular endothelial growth factor inhibition and how this affects tumor angiogenesis. The major clinical trials that have examined antivascular endothelial growth factor agents to treat patients with advanced colorectal cancer will then be described. Finally, there is a commentary regarding the status of targeted agents currently in development for the treatment of advanced colorectal cancer and a discussion of the potential future considerations for the use of antivascular endothelial growth factor agents in clinical practice.     

Anti-VEGF therapy: a new approach to colorectal cancer therapy

The purpose of this review is to discuss the inhibition of vascular endothelial growth factor as a treatment for advanced colorectal cancer. The review will begin by summarizing the theory behind vascular endothelial growth factor inhibition and how this affects tumor angiogenesis. The major clinical trials that have examined antivascular endothelial growth factor agents to treat patients with advanced colorectal cancer will then be described. Finally, there is a commentary regarding the status of targeted agents currently in development for the treatment of advanced colorectal cancer and a discussion of the potential future considerations for the use of antivascular endothelial growth factor agents in clinical practice.     

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.     

Anti-Angiogenic Strategies in Breast Cancer: An Update

Angiogenesis plays a role in primary tumor growth and metastatic potential of breast cancer, and within the past decade, the development of angiogenesis inhibitors has been a significant focus of clinical research efforts. Multiple studies to date have confirmed a role for bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with chemotherapy in the treatment of metastatic breast cancer. Efforts to determine the efficacy of second-generation VEGF receptor antagonists in breast cancer patients are ongoing. In addition, trials are underway to investigate potential synergy between anti-angiogenic agents and other classes of breast cancer therapeutics and to examine the efficacy of angiogenesis inhibition in nonmetastatic disease. Preliminary work evaluating predictors of response to therapy, including serologic biomarkers, class-effect toxicity, or dynamic radiologic change, and pharmacogenetics, has been promising; however, future study is critical to best identify the patient population most likely to benefit from anti-angiogenic therapy.     

The present and future of angiogenesis-directed treatments of colorectal cancer

The level of angiogenic activity in colorectal tumors has been shown to be a determinant of survival. Recent trials established that, in both the first- and second-line treatment of metastatic colorectal cancer, the addition of the vascular endothelial growth factor (VEGF)-directed antibody bevacizumab to chemotherapy significantly prolongs survival compared to chemotherapy alone. Those trials provided proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment of this disease. Oral agents directed toward VEGF receptor signaling are in advanced development, but none to date has proven beneficial in phase III trials in advanced colorectal cancer. Additional trials are needed to determine if improved pharmacological characteristics of the small molecules can be modified to replicate the activity of the antibody or if mechanistic differences require a more specific approach. Since bevacizumab has minimal activity as a single agent, a key question for future therapeutic development relates to the interaction between antiangiogenic strategies and cytotoxic therapies. We hypothesize that bevacizumab may potentiate the efficacy of cytotoxics not solely by alterations of tumor interstitial pressure but also by promoting sensitivity to proapoptotic signals consequent upon nutrient and oxygen withdrawal.     

Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer

Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis and has become an important target for anticancer treatment. In 2004, this approach was validated in a randomized, controlled phase III clinical trial. It was shown that the addition of bevacizumab, a humanized monoclonal antibody against VEGF-A, to conventional chemotherapy prolonged survival over chemotherapy alone in patients with metastatic colorectal cancer. In this review, we discuss the results of the clinical trials that have led to the incorporation of antiangiogenic agents into the treatment of patients with advanced colorectal cancer. We limit ourselves to the two agents that have been tested extensively in phase III trials: bevacizumab and vatalanib, a small molecule tyrosine kinase inhibitor against VEGF receptors. In addition, we discuss the adverse effects of bevacizumab and vatalanib and the clinical management of the side effects.     

p53、血管内皮生长因子在大肠癌组织中的表达与血管生成

目的　探讨p53、血管内皮生长因子 (VEGF)在大肠癌组织中的表达及其与血管生成的关系。方法　利用免疫组化SABC法 ,对 1 0 6例大肠癌组织及 2 0例正常大肠组织中的 p53、VEGF的表达及微血管密度 (MVD)进行研究。 结果　p53、VEGF的表达与肿瘤的分化程度及Dukes分期无明显相关性 (P >0 .0 5 )。p53表达阳性或VEGF表达阳性的大肠癌组织MVD明显高于p53表达阴性 (P <0 .0 1 )或VEGF表达阴性者 (P <0 .0 1 )。p53表达阳性的大肠癌组织中VEGF的表达阳性率显著高于 p53表达阴性者 (P <0 .0 1 )。结论　p53、VEGF在大肠癌的发生和发展中起着重要作用 ,可反映大肠癌的恶性程度和进展情况并作为预后的指标 ,p53作用的发挥是通过上调VEGF的表达水平来实现的