Comparative efficacy of antiangiogenic treatment for newly diagnosed glioblastoma: A protocol for systematic review and network meta-analysis.

BACKGROUND: Glioblastoma is the most common malignant primary brain tumor which has highly expressed vascular endothelial growth factor. To date, various antiangiogenic drugs have been investigated in clinical trials but with no overall conclusion, especially for newly diagnosed glioblastoma (nGBM). In this study, Bayesian network meta-analysis will be used to conduct a comprehensive analysis of the results of different clinical trials, and assess the efficacy of different antiangiogenic drugs on nGBM. METHODS: In order to find more comprehensive information about the application of antiangiogenic drugs in nGBM patients, we searched the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials. We also reviewed their reference lists to avoid omissions. Cochrane risk of bias tool (V.1.4.3) and Stata (V.15.0) will be used to assess the methodological quality of this review. RESULTS: This study will provide reliable evidence for different antiangiogenic therapies in nGBM patients. CONCLUSION: We will evaluate the relative effectiveness of different antiangiogenic drugs and rank each intervention in nGBM patients through prognosis to provide decision-making reference on which method to choose for clinicians. PROTOCOL REGISTRATION NUMBER: CRD42019146537.

[Anti-VEGF therapy resistance in neovascular age-related macular degeneration]. / Rezistentnost' k anti-VEGF-terapii pri ékssudativnoi vozrastnoi makuliarnoi degeneratsii.

With account to the increase in the elderly population in most of the developed countries, the WHO defines age-related macular degeneration (AMD) as one of the main causes of blindness in the world. A large percentage of disability is accounted for by exudative, or neovascular, form of AMD. Today, a total of 5 anti-VEGF drugs exist that are recommended for treatment of exudative AMD: pegaptanib, ranibizumab, bevacizumab, aflibercept, and conbercept. Despite significant progress in the treatment of neovascular AMD yielded by the introduction into clinical practice of anti-VEGF drugs, some patients report a lack (down to complete lack) of response with standard treatment patterns and even a decrease in treatment efficacy after repeated intravitreal injections.

[Vascular endothelial growth factor inhibitors in the treatment of neovascular age-related macular degeneration]. / Primenenie blokatorov éndotelial'nogo faktora rosta sosudov pri lechenii vozrastnoĭ neovaskuliarnoĭ makuliarnoĭ degeneratsii.

Neovascular age-related macular degeneration (AMD) is the leading cause of vision loss in older patients. An important role in angiogenesis is played by regulatory mechanisms (an increase in the number of proliferating endothelial and stromal cells and morphological alterations in the vascular network) induced by factors from the vascular endothelial growth factor (VEGF) family. Since 2006, the key treatment of neovascular AMD includes agents that inhibit the activity of VEGF. This review covers the effectiveness and safety of the use of anti-VEGF agents in neovascular AMD patients. A comparison is drawn between monoclonal antibody-based therapy and a new drug from the VEGF-Trap group.

[Role of genetic markers in personalization of anti-angiogenic therapy in patients with exudative age-related macular degeneration]. / Rol' geneticheskikh markerov v personalizatsii antiangiogennoi terapii ékssudativnoi formy vozrastnoi makuliarnoi degeneratsii.

The review presents data of clinical and pharmacogenetic research by Russian and foreign authors conducted within the last three years on the effectiveness of anti-angiogenic treatment against wet age-related macular degeneration (AMD). Scientific results on the association between angiogenesis-related gene polymorphisms responsible for predisposition to AMD on the one hand and a positive response to anti-VEGF therapy on the other are presented. Particular attention is paid to the main regulator of angiogenesis - the VEGF-A gene.

[Anti-angiogenic therapies: from theory to practice]. / Les thérapies anti-angiogéniques: de la théorie à la pratique.

During recent years clear progress has been made in support of tumor pathology. However, the treatment of metastatic disease is now a real therapeutic challenge. Among the new therapeutic strategies, blocking angiogenesis has been the subject of numerous clinical trials. However, if this approach was validated in 2004 by the approval of the first humanized anti-VEGF antibody (bevacizumab or Avastin(®), Roche, 2004), the pre-clinical and clinical studies conducted in the last 5 years have moderated the enthusiasm that these therapies had led in the early 2000s. In November 2011, the US Food and drug administration (FDA) revoke the agency's approval of the breast cancer indication for Avastin(®) because of benefit-risk balance appears negative. This review describes successively the mechanisms of action of antiangiogenic agents, the main anti-angiogenic drugs and the theoretical advantages and practical limitations of these therapies.

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

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

Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors.

Inhibiting angiogenesis has become an important therapeutic strategy for cancer treatment but, like other current targeted therapies, benefits experienced for late-stage cancers can be curtailed by inherent refractoriness or by acquired drug resistance, requiring a need for better mechanistic understanding of such effects. Numerous preclinical studies have demonstrated that VEGF pathway inhibitors suppress primary tumour growth and metastasis. However, it has been recently reported that short-term VEGF and VEGFR inhibition can paradoxically accelerate tumour invasiveness and metastasis in certain models. Here we comprehensively compare the effects of both antibody and small molecule receptor tyrosine kinase (RTK) inhibitors targeting the VEGF-VEGFR pathway, using short-term therapy in various mouse models of metastasis. Our findings demonstrate that antibody inhibition of VEGF pathway molecules does not promote metastasis, in contrast to selected small molecule RTK inhibitors at elevated-therapeutic drug dosages. In particular, a multi-targeted RTK inhibitor, sunitinib, which most profoundly potentiated metastasis, also increased lung vascular permeability and promoted tumour cell extravasation. Mechanistically, sunitinib, but not anti-VEGF treatment, attenuated endothelial barrier function in culture and caused a global inhibition of protein tyrosine phosphorylation, including molecules important for maintaining endothelial cell-cell junctions. Together these findings indicate that, rather than a specific consequence of inhibiting the VEGF signalling pathway, pharmacological inhibitors of the VEGF pathway can have dose- and drug class-dependent side-effects on the host vasculature. These findings also advocate for the continued identification of mechanisms of resistance to anti-angiogenics and for therapy development to overcome it.

Classification and toxicities of vascular disrupting agents.

Vascular disrupting agents (VDAs) are an exciting new group of targeted therapies under active clinical research in many solid tumors, in particular, lung cancer. Small-molecule VDAs are the focus of current clinical research, and consist of the flavonoids and the tubulin-binding agents. Toxicities of single-agent VDAs are characterized by acute, transient, and generally noncumulative side effects including headaches, nausea and vomiting, tumor pain, hypertension, and tachycardia. Flavonoid agents can also cause infusion site pain, visual disturbances, electrocardiac abnormalities, and symptoms consistent with an acute release of serotonin. Tubulin-binding agents can result in cardiac ischemia, abdominal pain, neuromotor abnormalities and cerebellar ataxia, and acute hemodynamic changes. Clinical trials investigating VDAs in combination with traditional chemotherapy have also shown the potential for significant pharmacologic and adverse toxicity interactions. Further research will need to focus on pharmacokinetic and pharmacodynamic parameters to optimize dosing schedules, determine effective combinations with chemotherapy, and minimize toxicities associated with VDAs.

The discovery of antiangiogenic molecules: a historical review.

In a landmark publication of 1971, Folkman proposed antiangiogenesis as a potential target in cancer biology [1]. Over the past 30 years most research on tumor angiogenesis has been aimed at inhibiting the process of tumor-induced vessel formation. The first angiogenesis inhibitor, bevacizumab, was approved by the Food and Drug Administration in 2004 for the treatment of metastatic carcinoma of the colon-rectum. Antiangiogenesis remains a dynamic and evolving field in oncology. New therapeutic targets continue to emerge followed by the rapid development of new therapeutic agents to be investigated in clinical trials.

Antiangiogenesis, anti-VEGF(R) and outlook.

Tumor angiogenesis and antiangiogenesis has moved from an exotic research topic into clinical practice defining a new and promising avenue of targeted cancer therapy. Starting with a historical perspective on tumor angiogenesis, this review provides the basic concepts and classification of angiogenesis inhibition. Focusing primarily on vascular endothelial growth factor (VEGF), the biological activity and regulation of the gene expression of VEGF, its isoforms, and the receptors are summarized. Furthermore, naturally occurring modulators are listed, an overview on angiogenesis inhibitors in clinical trails is provided, and finally a brief outlook is given on this fascinating and rapidly evolving field of oncology.

Curcumin as an inhibitor of angiogenesis.

Angiogenesis, the formation of new blood vessels from host vasculature, is critical for tumor growth and metastases. -Curcumin, a novel small-molecular-weight compound, has been shown to inhibit carcinogenesis in different organs and the common link between these actions is its antiangiogenic effect. Curcumin is a direct inhibitor of angiogenesis and also downregulates various proangiogenic proteins like vascular endothelial growth factor and basic fibroblast growth factor. Curcumin's antiangiogenic effect is also in part due to its inhibitory effect on signal transduction pathways, including those involving protein kinase C and the transcription factors NF-kappaB and AP-1. Curcumin has an inhibitory effect on two groups of proteinases involved in angiogenesis that are the members of the matrix metalloproteinase family and the urokinase plasminogen activator family. Cell adhesion molecules are upregulated in active angiogenesis and curcumin can block'this effect, adding further dimensions to curcumin's antiangiogenic effect. Curcumin shows a dose-dependent inhibition on tumor necrosis factor, a versatile cytokine, which has its effect on angiogenesis through the signal transduction pathways, expression of proangiogenic factors, and cell adhesion molecules. Curcumin's effect on the overall process of angiogenesis compounds its enormous potential as an antiangiogenic drug.

[Rationale of antiangiogenic therapy]. / Az antivaszkuláris terápia elvi alapjai.

Vascularization of cancer is a complex and heterogenous process where neoangiogenesis by sprouting is only one of the possible mechanisms that also include postnatal vasculogenesis, vessel incorporation, intussusceptive microvascular growth, glomeruloid angiogenesis and vascular mimicry. Furthermore, the mechanism of vascularization may also depend on the cancer type and the host tissue as well. Antivascular agents can be divided into angiosuppressive ones (endothelial cell proliferation inhibitors), vascular-targeted agents (microvessel disrupting agents) and anti-hypoxia agents (targeting the molecular pathways responsible for the development of the angiogenic phenotype). Since antivascular therapy is a special form of targeted therapy, it is necessary to apply it in a rational manner to consider the type of vascularization, the molecular background of the angiogenic phenotype, the stage of the disease and the standard anticancer therapy. Whithout such a fine-tuning, antivascular therapies cannot be integrated more successfully into the management of cancer patients.

VEGF-targeted therapy: therapeutic potential and recent advances.

After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumors requires constant vascular growth and remodeling in order for solid tumors to grow beyond 1-2 mm(3) in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which makes them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.

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.

[Antiangiogenic treatment of cancer]. / Tratamiento antiangiogénico del cáncer.

The process of formation of new vessels from pre-existing capillaries is called angiogenesis. Angiogenesis is a complex process which involves distinct cells, soluble components and factors related to the extra-cellular matrix and which is highly important in a large variety of physiological and pathological processes in the body. Angiogenesis regulation takes place through a perfect equilibrium between the production and release of different stimulatory and inhibitory factors which vary in relation to needs and tissue types. A large number of diseases are characterized by alterations in the angiogenic process, either by an insufficiency or by excessive angiogenesis. The requirement of blood vessel proliferation for tumor growth was observed more than a century ago. Angiogenic treatment would have an indirect antitumoral action, inhibiting tumor vascularization and impairing the supply of essential nutrients for tumoral growth and development.