Antiangiogenic cancer therapy

Like most embryonic tissues, tumors have the ability to build up their own blood vessel networks. However, the architecture of tumor vessels is fundamentally different from that found in healthy tissues. Tumor vessels are usually irregular, heterogeneous, leaky, and poorly associated with mural cells. Endothelial cells in tumor vessels are also disorganized and express imbalanced surface molecules. These unusual features may provide some molecular and structural basis for selective inhibition or even destruction of tumor vessels by angiogenesis inhibitors. In animal tumor models, several angiogenesis inhibitors seem to inhibit tumor angiogenesis specifically without obvious effects on the normal vasculature. As a result, these inhibitors produced potent antitumor effects in mice. Excited by these preclinical studies, more than 60 angiogenesis inhibitors are being evaluated for their anticancer effects in human patients. Although the ultimate outcome of antiangiogenic clinical trials remains to be seen, several early observations have reported some disappointing results. These early clinical data have raised several important questions. Can we cure human cancers with angiogenesis inhibitors? Have we found the ideal angiogenesis inhibitors for therapy? What is the difference between angiogenesis in an implanted mouse tumor and in a spontaneous human tumor? What are the molecular mechanisms of these angiogenesis inhibitors? Should angiogenesis inhibitors be used alone or in combinations with other existing anticancer drugs? In this review, we will discuss these important issues in relation to ongoing antiangiogenic clinical trials.     

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.     

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.     

Antiangiogéniques et métastases cérébrales: plus de peur que de mal ?

Brain metastases occur in 5% to 20% of cancer patients, depending on the primary tumor type. Several angiogenesis inhibitors have shown clinical efficacy in numerous tumors that frequently metastasize to the brain. However, clinical trials of such angiogenesis inhibitors have excluded patients with brain metastases owing to the theoretical risk of cerebral hemorrhage. Therefore, the available safety data are mainly retrospective: cerebral hemorrhage incidence is estimated to affect 0.1% to 3% of patients treated with angiogenesis inhibitors. Efficacy data are scarce, but case reports of brain metastases with complete and partial responses have been published. Few retrospective reports with few patients suggest that radiation therapy or radiosurgery could be safe. Therefore, available safety data suggest that angiogenesis inhibitor can be used to treat cancer patients with brain metastases. Prospective evaluation is warranted, and cancer patients who harbor brain metastases should not be systematically excluded from prospective clinical trials evaluating angiogenesis inhibitors.     

Recent advances in the treatment of pediatric brain tumors

Central nervous system (CNS) cancers are the second most frequent malignancy (and the most common solid tumor) in childhood. In recent years, significant advances in surgery, radiotherapy, and chemotherapy have improved survival in children with these tumors. However, a significant proportion of patients with CNS tumors suffer progressive disease despite such treatment. Advances in the understanding of the nature of the blood-brain/tumor barrier, chemotherapy resistance, tumor biology, and the role of angiogenesis in tumor progression and metastases have led to the advent of newer therapeutic strategies that circumvent these obstacles or target specific receptors that control signal transduction and/or angiogenesis in tumor cells. Ongoing clinical trials will determine whether these novel treatment modalities will improve outcomes for children with brain tumors.     

The potential role of antivascular therapy in the adjuvant and neoadjuvant treatment of cancer

Antivascular therapy may be considered as one of the most promising approaches in the treatment of cancer. Antivascular treatment may be divided in antiangiogenesis and vascular targeting. Antiangiogenic therapy prevents neovascularization by inhibiting proliferation, migration, and/or differentiation of endothelial cells. Vascular targeting is directed at the existing tumor vasculature. Several inhibitors of angiogenesis are currently being tested in clinical cancer trials. The challenge for the next decade is to incorporate antivascular approaches into conventional treatment strategies. This review will summarize the conceptual basis of antivascular therapy and discuss the potential role of these agents in the adjuvant, neoadjuvant, and perioperative treatment of cancer.     

Anti-angiogenic Therapy in Pediatric Neuro-oncology

Summary In order to grow, tissues require additional nutrients and oxygen as well as removal of waste products. Tumors achieve this by up-regulating angiogenic cytokines and/or down-regulating natural inhibitory proteins that allow neovascularization to proceed. Brain tumors continue to account for significant morbidity and mortality, in spite of significant advances in neurosurgical and radiation techniques and new chemotherapy combinations. As such, there is a real and immediate need for novel biologic therapies that can target these tumors. A number of new drugs that target different aspects of the angiogenic cascade have been identified and are now in clinical trials in children with primary brain tumors. In many of these pre-clinical and clinical studies, anti-angiogenic therapy has been well tolerated, has lacked many of the traditional toxicities of radiation and chemotherapy, does not require blood–brain barrier penetration, and targets a critical pathway in central nervous system tumor development. This review will discuss what angiogenesis is, how pediatric brain tumors regulate angiogenesis to obtain a vascular supply, what types of inhibitors are available, how different classes of inhibitors work, the types of resistance possible, how rapidly these inhibitors may work, and what surrogate markers of activity are available to follow response.     

New treatment strategies for malignant gliomas

Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma multiforme, the most common grade of malignant glioma, is 10–12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy. Several low molecular weight signal transduction inhibitors have been examined in preclinical and clinical malignant glioma trials. The efficacy of these agents as monotherapies has been modest, at best; however, small subsets of patients who harbor specific genetic changes in their tumors may display favorable clinical responses to defined small molecule inhibitors. Multitargeted kinase inhibitors or combinations of agents targeting different mitogenic pathways may overcome the resistance of tumors to single-agent targeted therapies. Well designed studies of small molecule kinase inhibitors will include assessment of safety, drug delivery, target inhibition and correlative biomarkers to define mechanisms of response or resistance to these agents. Predictive biomarkers will enrich for patients most likely to respond in future clinical trials. Additional clinical studies will combine novel targeted therapies with radiation, chemotherapies and immunotherapies.     

New treatment strategies for malignant gliomas

Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma multiforme, the most common grade of malignant glioma, is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy. Several low molecular weight signal transduction inhibitors have been examined in preclinical and clinical malignant glioma trials. The efficacy of these agents as monotherapies has been modest, at best; however, small subsets of patients who harbor specific genetic changes in their tumors may display favorable clinical responses to defined small molecule inhibitors. Multitargeted kinase inhibitors or combinations of agents targeting different mitogenic pathways may overcome the resistance of tumors to single-agent targeted therapies. Well designed studies of small molecule kinase inhibitors will include assessment of safety, drug delivery, target inhibition and correlative biomarkers to define mechanisms of response or resistance to these agents. Predictive biomarkers will enrich for patients most likely to respond in future clinical trials. Additional clinical studies will combine novel targeted therapies with radiation, chemotherapies and immunotherapies.     

Antiangiogenic strategies and agents in clinical trials

The understanding that the growth of tumors depends on the acquisition of a blood supply has led to the development of new therapies for cancer and other angiogenic diseases based on inhibition of neovascularization. This review examines the role of angiogenesis in cancer progression and describes various strategies for interfering with this process. The developmental status of angiogenesis inhibitors in human clinical trials is presented, including their proposed mechanisms of action. Standard chemotherapeutic agents and angiogenesis inhibitors are compared, noting that different end points might need to be considered in clinical trials and that drug resistance may be less of a problem with antiangiogenic therapy than with conventional chemotherapy regimens. The suggestion is made that cytotoxic chemotherapy and angiogenesis inhibitors used in combination may produce complementary therapeutic benefits in the treatment of cancer.     

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2: PI3K/Akt/PTEN, mTOR, SHH/PTCH and angiogenesis

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Activity of the phosphoinositide 3; kinase (PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimulation by growth factor receptors and Ras. Loss of function of the tumor suppressor gene PTEN also frequently contributes to upregulation of PI3K/Akt. Several compounds, such as wortmannin and LY-294002, can target PI3K and inhibit activity of this pathway. The mammalian target of rapamycin (mTOR) is an important regulator of cell growth and metabolism and is often upregulated by Akt. Clinical trials of CCI-779, an inhibitor of mTOR, are ongoing in recurrent malignant glioma patients. The sonic hedgehog/PTCH pathway is involved in the tumorigenesis of some familial and sporadic medulloblastomas. This pathway can be targeted by cyclopamine, which is under evaluation in preclinical studies. Angiogenesis is a critical process for development and progression of brain tumors. Targeted approaches to inhibit angiogenesis include monoclonal antibodies, receptor tyrosine kinase inhibitors, antisense oligonucleotides and gene therapy. Clinical trials are ongoing for numerous angiogenesis inhibitors, including thalidomide, CC-5103 and PTK 787/ZK 222584. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.     

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.     

Gene transfer technologies for malignant gliomas.

Although early clinical gene therapy trials for recurrent central nervous system neoplasms showed the proof-of-principle, they did not fulfill the high expectations suggested by the preclinical experimental data. Insufficient distribution of vectors in human brain tumors and very low transduction efficiency require that we reevaluate gene transfer concepts for brain tumor treatment. Major steps to improve gene transfer into the central nervous system and the efficacy of gene therapy for malignant brain tumors include: 1) the design of more effective vector systems; 2) the development of new or improved prodrug/suicide systems, gene replacement approaches, or strategies targeting the immune response or tumor angiogenesis; 3) the study of new techniques to enhance delivery of genetic vectors into brain tumors and for monitoring gene delivery into tumors; and 4) assessment of the role of gene therapy as part of a combined treatment approach.     

Angiogenesehemmung in der Onkologie

Targeted therapies against cancer have become more and more important. In particular, the inhibition of tumor angiogenesis has been the focus of new treatment strategies. Numerous new substances have been developed as angiogenesis inhibitors and evaluated in clinical trials for safety, tolerance and efficacy. With positive study results, some of these molecules have already been approved for clinical use. This is true for the VEGF neutralising antibody bevacizumab in metastatic colorectal cancer, as well as the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cancer, and, in the case of sunitinib, also for gastrointestinal stroma tumors. Specific toxicity profile and the high cost for these new therapeutics require a careful selection of patients, including consideration of possible benefits and risks on a individual basis.     

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.     

Src continues aging: current and future clinical directions.

Aberrant activation of members of the Src family of nonreceptor protein tyrosine kinases is common in solid tumor malignancies and may contribute to the development and/or progression of these tumors. As a result, four Src inhibitors are now in more than 50 clinical trials for at least 14 different types of solid tumors. In this review, we briefly discuss the preclinical rationale for Src inhibitors, the development strategies most likely to be successful in the clinic, and the rationale for Src inhibitors in combination with other agents as part of a more comprehensive therapeutic strategy. As the use of Src family inhibitors in clinical trials on solid tumors is in its infancy, further studies on the roles of Src family kinases in tumor progression, chemoresistance, epidermal-to-mesenchymal transition, and other properties of tumor progression will be important in designing the most effective clinical trials using these inhibitors.     

Clinical biomarkers of angiogenesis inhibition

INTRODUCTION: An expanding understanding of the importance of angiogenesis in oncology and the development of numerous angiogenesis inhibitors are driving the search for biomarkers of angiogenesis. We review currently available candidate biomarkers and surrogate markers of anti-angiogenic agent effect. DISCUSSION: A number of invasive, minimally invasive, and non-invasive tools are described with their potential benefits and limitations. Diverse markers can evaluate tumor tissue or biological fluids, or specialized imaging modalities. CONCLUSIONS: The inclusion of these markers into clinical trials may provide insight into appropriate dosing for desired biological effects, appropriate timing of additional therapy, prediction of individual response to an agent, insight into the interaction of chemotherapy and radiation following exposure to these agents, and perhaps most importantly, a better understanding of the complex nature of angiogenesis in human tumors. While many markers have potential for clinical use, it is not yet clear which marker or combination of markers will prove most useful.     

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.     

Molecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors. Part 3: brain tumor invasiveness

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Cellular invasion of surrounding brain is one of the key features of brain tumor behavior and is currently under evaluation for potential therapeutic targets. Tumor invasion occurs in the context of the extracellular matrix (ECM) of the brain and involves the interaction between cell-surface adhesion molecules, such as integrins and proteins embedded within the ECM. The overexpression of integrins is often associated with invasive behavior and can be inhibited by targeted approaches such as antibodies, antisense constructs and cyclic peptides. Tumor cell-secreted matrix metalloproteinases and serine proteinases degrade ECM proteins and provide space for movement and infiltration. The expression of proteinases positively correlates with tumor grade and infiltrative capacity. Proteinase activity can be reduced by several methods, including antibodies and small-molecule inhibitors such as marimastat. Early clinical trials suggest that marimastat may have activity in combination with traditional chemotherapy regimens. Further development of targeted therapies designed to inhibit tumor infiltration, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with brain tumors.     

Molecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors. Part 3: brain tumor invasiveness

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Cellular invasion of surrounding brain is one of the key features of brain tumor behavior and is currently under evaluation for potential therapeutic targets. Tumor invasion occurs in the context of the extracellular matrix (ECM) of the brain and involves the interaction between cell-surface adhesion molecules, such as integrins and proteins embedded within the ECM. The overexpression of integrins is often associated with invasive behavior and can be inhibited by targeted approaches such as antibodies, antisense constructs and cyclic peptides. Tumor cell-secreted matrix metalloproteinases and serine proteinases degrade ECM proteins and provide space for movement and infiltration. The expression of proteinases positively correlates with tumor grade and infiltrative capacity. Proteinase activity can be reduced by several methods, including antibodies and small-molecule inhibitors such as marimastat. Early clinical trials suggest that marimastat may have activity in combination with traditional chemotherapy regimens. Further development of targeted therapies designed to inhibit tumor infiltration, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with brain tumors.