Development of new drugs in angiogenesis

Angiogenesis, the growth of new capillaries from pre-existing vessels, contributes to the development and progression of a variety of physio-pathological conditions. There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. Conversely, therapeutic angiogenesis is an important homeostatic response contributing to limit the damage to ischemic tissues. Molecular processes involved in angiogenesis include stimulation of endothelial growth by cytokine production (i.e. vascular endothelial growth factor, VEGF; fibroblast growth factor-2, FGF-2), degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), and migration of endothelial cells mediated by integrins (cell membrane adhesion molecules). Drugs targeting pathologic angiogenesis have been designed to interfere with any of these steps and are currently undergoing evaluation in early clinical studies. Important therapeutic strategies are: suppression of activity and signaling pathways activated by the major angiogenic regulators like VEGF and FGF-2; inhibition of function of alphav-integrins and MMPs; exploitation of endogenous anti-angiogenic molecules like angiostatin and endostatin. The strategy to "silence" endothelium with antiangiogenic drugs to starve tumors, provides a novel approach for cancer treatment. The unique targets of these drugs (endothelium) make them distinct from traditional cytotoxic chemotherapeutic agents. Conversely, gene transfer of angiogenesis inducers is the new approach for therapeutic neovascularization, which is under investigation using a variety of growth factors and a wide array of potential delivery systems, including the application of the gene as naked DNA or by viral vector. The status of pro- and anti-angiogenic therapies is here presented and discussed.     

Selective genetic analysis of myoma pseudocapsule and potential biological impact on uterine fibroid medical therapy

Introduction: Tumor-associated angiogenesis is one of the essential hallmarks underlying cancer development and metastasis. Anti-angiogenic agents accordingly aim to restrain cancer progression by blocking the formation of new vessels, improving the delivery of chemotherapeutic agents to the tumor site and reducing the shedding of metastatic cells into the circulation. This review article addresses some key issues in the use of angiogenesis inhibitors in cancer.

Areas covered: The authors review the complex interactions between cell signaling pathways involved in tumor angiogenesis, and focus in particular on the molecular mechanisms that may induce resistance to angiogenesis inhibitors. They will also discuss some novel therapeutic strategies evolving within anti-angiogenic therapy such as the targeting of VEGFR-3, endothelial integrins and hepatocyte growth factor-MET signaling.

Expert opinion: Although anti-angiogenic therapy is targeted at the non-malignant part of the tumor, the intricate network of growth promoting signaling pathways and in particular the redundancy when single pathways are targeted in endothelial cells represents a major therapeutic obstacle. A key challenge will be to develop more efficient inhibitors, combined with an individualized approach based on each tumor's own endothelial signaling profile. Furthermore, reliable biomarkers which pinpoint those patients that will benefit from anti-angiogenic therapy need to be identified.     

Evading tumor evasion: Current concepts and perspectives of anti-angiogenic cancer therapy

Within three decades, anti-angiogenic therapy has rapidly evolved into an integral component of current standard anti-cancer treatment. Anti-angiogenic therapy has fulfilled a number of its earlier proposed promises. The universality of this approach is demonstrated by the broad spectrum of malignant and benign tumor entities, as well as non-neoplastic diseases, that are currently treated with anti-angiogenic agents. In contrast to tumor cell targeting therapies, the development of acquired drug resistance (e.g., via mutations in growth factor receptor signaling genes) has not been described yet for the principal target of anti-angiogenic therapy—the tumor endothelium. Moreover, the tumor endothelium has emerged as a critical target of conventional cancer therapies, such as chemotherapy and radiotherapy. The presumption that tumor growth and metastasis are angiogenesis-dependent implies that the number of potential targets of an anti-cancer therapy could be reduced to those that stimulate the angiogenesis process. Therefore, the set of endogenous angiogenesis stimulants might constitute an “Achilles heel” of cancer. Direct targeting of tumor endothelium via, e.g., endogenous angiogenesis inhibitors poses another promising but clinically less explored therapeutic strategy. Indeed, the majority of current anti-angiogenic approaches block the activity of a single or at most a few pro-angiogenic proteins secreted by tumor cells or the tumor stroma. Based on our systems biology work on the angiogenic switch, we predicted that the redundancy of angiogenic signals might limit the efficacy of anti-angiogenic monotherapies. In support of this hypothesis, emerging experimental evidence suggests that tumors may become refractory or even evade the inhibition of a single pro-angiogenic pathway via compensatory upregulation of alternative angiogenic factors. Here, we discuss current concepts and propose novel strategies to overcome tumor evasion of anti-angiogenic therapy. We believe that early detection of tumors, prediction of tumor evasive mechanisms and rational design of anti-angiogenic combinations will direct anti-angiogenic therapy towards its ultimate goal—the conversion of cancer to a dormant, chronic, manageable disease.     

Cancer anti-angiogenic therapy

Tumor angiogenesis affords new targets for cancer therapy, since inhibition of angiogenesis suppresses tumor growth by cutting out the supply of oxygen and nutrients. Anti-angiogenic therapy is thought to be free of the severe side effects that are usually seen with cytotoxic anticancer drugs. Furthermore, anti-angiogenic therapy is thought not only to eradicate primary tumor tissues, but also to suppress tumor metastases. However, it is uncertain whether this therapy causes tumor regression because it inhibits only angiogenic events. Recently, a novel anti-angiogenic therapy called anti-neovascular therapy (ANET) has become notable. This therapy inflicts indirect lethal damage on tumor cells by damaging newly formed blood vessels using anti-cancer drugs targeting the angiogenic vasculature, since cytotoxic anti-cancer drugs cause damage to proliferating neovascular endothelial cells as well as tumor cells. Moreover, neovascular endothelial cells would not be expected to acquire drug-resistance. Traditional chemotherapy, which directly targets tumor cells, has potential problems such as low specificity and severe side effects. On the contrary, in ANET, severe side effects may be suppressed, since traditional anti-cancer agents are delivered to the neovessels by DDS technology. Besides the usage of DDS technology, anti-neovascular scheduling of chemotherapy, or metronomic-dosing chemotherapy, has also been attempted in which anti-cancer drugs are administered on a schedule to damage neovessels. In this review, we describe traditional anti-angiogenic therapy and ANET. We also discuss anti-angiogenic cancer photodynamic therapy (PDT), since PDT is clinically applied to treat age-related macular degeneration (AMD), in which uncontrolled angiogenesis occurs.     

Cytokines as anti-angiogenic agents in haematological malignancies

The role of angiogenesis in haematological malignancies has been recently recognized. In these tumors, angiogenesis has been investigated predominantly in the bone marrow (BM) compartment where it appears to be regulated by multiple interactions between malignant cells and different cell populations present in the tumor microenvironment. Thus, angiogenesis represents a therapeutic target that opens new perspectives for the treatment of haematological malignancies. Cytokines are small proteins that mediate intercellular communications, thus regulating important cellular functions, such as immune responses and angiogenesis. Some cytokines show anti-angiogenic properties through different mechanisms; these cytokines can interfere directly with biological functions of endothelial cells and/or target tumor cells inhibiting their capability to stimulate formation of new microvessels that are essential for tumor growth and dissemination. In this review we will summarize the current knowledge about the role of cytokines as anti-angiogenic agents in cancer, focusing our attention on the anti-angiogenic activity of IL-12 family members in haematological malignancies.     

Anti-angiogenic therapy as a cancer treatment paradigm

The inhibition of angiogenesis is an emerging therapeutic strategy for cancer treatment. In contrast to conventional therapies, anti-angiogenic therapies primarily target tumor-associated endothelial cells which serve as a lifeline for tumor growth, progression and metastasis. By blocking the supply of essential nutrients and the removal of metabolites, anti-angiogenic therapies aim to delay both primary and metastastic tumor growth while overcoming the inherent cytotoxicities of classical chemotherapies. Indeed, tumor-related angiogenesis is a multi-step process initiated by a cascade of proangiogenic factors secreted from both the tumor and host tissues. These intricate processes involve a close interaction of tumor and associated endothelial cells as well as an intimate communication between proliferating endothelial cells, stromal cells and extracellular matrix components. Inhibition of these proangiogenic mechanisms has become a major challenge for the development of anti-cancer treatment modalities. In this regard, anti-angiogenic therapies embody a potentially powerful adjunct to traditional cancer therapies. In this review, we provide an overview of traditional anti-cancer drugs and discuss the fundamentals of anti-angiogenic therapies. While presenting the salient features of the anti-angiogenic agents targeting the individual phases of angiogenesis, we highlight the potential for specific agent development as novel anti-angiogenic therapeutics. Finally, we present and summarize emerging angiogenesis inhibitors.     

Anti-vascular tumor therapy: recent advances, pitfalls and clinical perspectives.

Anti-vascular tumor therapy represents a promising new strategy for cancer treatment. Anti-vascular treatment may be divided in anti-angiogenic and vascular targeting therapy. Whereas anti-angiogenic drugs aim on the inhibition of new vessel formation, vascular targeting compounds are designed to selectively destruct preexisting tumor blood vessels leading to secondary tumor cell death. Both anti-angiogenic drugs and vascular targeting agents have proven effective anti-tumoral activity in numerous preclinical studies over the last decade. In vivo, a combination with anti-vascular tumor therapy enhances the effects of other treatment modalities as chemo- and radiotherapy. Phase I clinical studies revealed a number of well-tolerated candidates. As monotherapy, however, anti-angiogenic treatment lacked efficacy in randomized clinical studies so far. In contrast, combination of anti-angiogenic therapy with chemotherapy was highly effective in an encouraging, large randomized phase III trial on metastatic colorectal cancer. This review will outline recent advances in the preclinical and clinical development of anti-vascular therapy with focus on vascular targeting. Conceptual differences between anti-angiogenic and vascular targeting therapies will be discussed with emphasis on specific problems and pitfalls in the conversion into the clinic.     

Angiogenesis inhibitors. Drug selectivity and target specificity

The critical role of angiogenesis in tumor development and progression has long been appreciated. The elucidation of the mechanisms of tumor angiogenesis and the emergence of anticancer drugs targeting the tumor vasculature has been a breakthrough in the treatment of several tumors in the last few years. Several novel molecules are being developed that target different aspects of angiogenesis. This review outlines the principle of anti-angiogenic therapies, illustrates the main mechanisms and complexity of growth signals involved in tumor angiogenesis, its interactions with hypoxia, stroma and tumor microenvironment. It provides a comprehensive review of clinical results obtained with anti-angiogenic agents (VEGF/VEGFR signaling inhibitors, direct angiogenesis inhibitors, vascular disrupting agents) and finally discusses the differences of the several approaches and their limitations due to the emergence of resistance.     

Advances in polymeric micelles for drug delivery and tumor targeting

A plethora of formulation techniques have been reported in the literature for targeting drugs to specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as well as active mechanisms. Some inherent properties of PMs, including size in the nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor allow PMs to be targeted to the tumor site by a passive mechanism called the enhanced permeability and retention effect. PMs formed from an amphiphilic block copolymer are suitable for encapsulation of poorly water-soluble, hydrophobic anticancer drugs. Other characteristics of PMs such as separate functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. PMs can be conjugated with many ligands such as antibody fragments, epidermal growth factors, α₂-glycoprotein, transferrin, and folate to target micelles to cancer cells. Application of heat or ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be directed toward tumor angiogenesis, which is a potentially promising target for anticancer drugs. PMs have been used for the delivery of many anticancer agents in preclinical and clinical studies. This review summarizes recently available information regarding targeting of anticancer drugs to the tumor site using PMs.From the Clinical EditorThis review summarizes recent developments related to targeted anticancer drug delivery to tumor sites using polymeric micelles via active and passive mechanisms. Polymeric micelles can be conjugated with diverse ligands such as antibodies fragments, epidermal growth factors, α2-glycoprotein, transferrin, folate to target micelles to cancer cells.     

Microtubule-targeting agents in angiogenesis: where do we stand?

Angiogenesis is a key event of tumor progression and metastasis and hence a target for cancer chemotherapy. Therapeutic strategies focused on angiogenesis include the discovery of new, targeted anti-angiogenic agents and the re-evaluation of conventional anti-cancer drugs. Here, we review the most recent studies investigating the molecular and cellular mechanisms responsible for the anti-angiogenic activity of microtubule-targeting agents (MTAs). These agents include some of the most widely used and effective antitumor drugs that are also among the most anti-angiogenic. In addition, we summarize the latest results of pre-clinical and clinical studies involving MTAs administered at low metronomic doses and in anti-angiogenic combination strategies. Finally, we discuss the future development of these agents, their clinical potential and their limitations.     

Targeting angiogenesis for the treatment of prostate cancer

INTRODUCTION: While multiple therapies exist that prolong the lives of men with advanced prostate cancer, none are curative. This had led to a search to uncover novel targets for prostate cancer therapy, distinct from those of traditional hormonal approaches, chemotherapies, immunotherapies and bone-targeting approaches. The process of tumor angiogenesis is one target that is being exploited for therapeutic gain. AREAS COVERED: The most promising anti-angiogenic approaches for treatment of prostate cancer, focusing on clinical development of selected agents. These include VEGF-directed therapies, tyrosine kinase inhibitors, tumor-vascular disrupting agents, immunomodulatory drugs and miscellaneous anti-angiogenic agents. While none of these drugs have yet entered the market for the treatment of prostate cancer, several are now being tested in Phase III registrational trials. EXPERT OPINION: The development of anti-angiogenic agents for prostate cancer has met with several challenges. This includes discordance between traditional prostate-specific antigen responses and clinical responses, which have clouded clinical trial design and interpretation, potential inadequate exposure to anti-angiogenic therapies with premature discontinuation of study drugs and the development of resistance to anti-angiogenic monotherapies. These barriers will hopefully be overcome with the advent of more potent agents, the use of dual angiogenesis inhibition and the design of more informative clinical trials.     

Novel approaches for targeted cancer therapy

The clinical use of chemotherapeutic agents against malignant tumors is successful in many cases but suffers from major drawbacks. One drawback is lack of selectivity, which leads to severe side effects and limited efficacy; and another is the emergence/selection of drug-resistance. To limit non-specific toxicity and to improve the efficiency of cancer therapy, "tumor markers", which are proteins generally overexpressed on the surface of tumor cells, can be selectively targeted. Growth factor receptors are one of the most extensively studied tumor markers. The implication of growth factor receptors in the pathogenesis and evolution of cancer has clearly been established and therefore, provides a rationale for therapeutic intervention. The targeting of cytotoxic substances to tumor markers with "magic bullets" is an old idea that raised high expectations but also disappointment. Over the past decade, newly gained understanding of mechanisms for targeted therapy have brought new hopes. Pharmacological agents that selectively target and block the action of growth factors and their receptors have been attempted, such as monoclonal antibodies (mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes-encapsulated drugs, and small molecule inhibitors. This review will focus on current developments of selective targeting and bypassing drug resistance in the management of growth factor receptor-overexpressing tumors.     

Novel targets for VEGF-independent anti-angiogenic drugs

INTRODUCTION: In the last decades, the active research in the field of tumor angiogenesis led to the development of a class of agents providing an effective inhibition of neovessels formation through the blockade of VEGF-related pathways. More recently, the identification of several non-VEGF factors such as PDGF, FGF, HGF, angiopoietins, ALK1/endoglin, endothelis and ephrins involved in tumor angiogenesis have emphasized the need to develop agents targeting multiple pro-angiogenic pathways. AREAS COVERED: This review aimed at summarizing the role of non-VEGF molecular pathways in targeting tumor angiogenesis. Preclinical and clinical data for investigational agents against non-VEGF targets have been reviewed emphasizing the role of combined inhibition strategies. EXPERT OPINION: Besides the successful development of drugs providing a specific VEGF blockade, novel agents targeting alternative angiogenesis-related pathways are being tested. Although it seems that the potential clinical usefulness of these novel compounds have been not yet fully investigated, sunitinib, sorafenib, pazopanib and other multikinase inhibitors have certainly displayed encouraging results. A more in-depth clarification of anti-angiogenic agents is still needed, in order to design the best clinical setting and schedule for target-based agents and possibly anticipate potential tools to overcome the emerging issue of anti-angiogenic drug resistance.     

Sorafenib for lung cancer: is the "Battle" still open?

In the recent years, the improved understanding of the biological relevance of angiogenesis as a major cancer hallmark led to the development of a heterogeneous group of agents targeting this key process. Among the anti-angiogenic drugs (including monoclonal antibodies such as Bevacizumab, and other molecules with different mechanism of action, such as the vascular disrupting agents Vadimezan), the tyrosine kinase inhibitors (TKIs, Sorafenib, Sunitinib, Pazopanib, and Axitinib), are commonly thought to inhibit angiogenesis through a most rational and promising approach. In this regard, many tyrosine kinase inibitors, such as Sorafenib, are multi-targeted, which allows for the inhibition of those multiple functional pathways which are considered to be critical for both tumor development and progression. Besides, this multi-targeted activity may theoretically increase efficacy but also toxicity. As a member of this group, Sorafenib has already been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma not suitable for locoregional treatment, and it is currently under investigation for advanced non small cell lung cancer (NSCLC), either alone or in combination with other biological/cytotoxic agents.     

Anti-angiogenic drug discovery: lessons from the past and thoughts for the future

INTRODUCTION: Since the pioneering work of Judah Folkman, the discovery of bevacizumab has introduced the use of anti-angiogenic agents as a new modality for the treatment of cancer. Currently, hundreds of clinical trials involving anti-angiogenic agents, targeting different elements of the tumour angiogenesis pathway, are underway. However, thus far, the benefits of anti-angiogenic therapy in unselected patient populations are often marginal with harmful side effects. AREAS COVERED: This article presents a detailed discussion of the lessons learnt from the use of bevacizumab and other VEGF pathway inhibitors in the clinical setting. Specifically, this article provides a review of the literature on anti-VEGF agents and other angiogenesis inhibitors used in pre-clinical and clinical trials for cancer treatment. EXPERT OPINION: Future anti-angiogenic drug design centres on multiple protein targets and combinations including: growth factors, hypoxia-inducible factor and tumour endothelial cell markers unique to the tumour vasculature. Furthermore, treatment dosing, scheduling and combination with radiation and chemotherapy require further investigation, as does the potential of treating early disease, and the development of biomarkers which accurately predict response to therapy. These are essential for the future development of these drugs with individualised therapy likely to be the ultimate goal.     

Anti-angiogenic drug discovery: lessons from the past and thoughts for the future

Introduction: Since the pioneering work of Judah Folkman, the discovery of bevacizumab has introduced the use of anti-angiogenic agents as a new modality for the treatment of cancer. Currently, hundreds of clinical trials involving anti-angiogenic agents, targeting different elements of the tumour angiogenesis pathway, are underway. However, thus far, the benefits of anti-angiogenic therapy in unselected patient populations are often marginal with harmful side effects.

Areas covered: This article presents a detailed discussion of the lessons learnt from the use of bevacizumab and other VEGF pathway inhibitors in the clinical setting. Specifically, this article provides a review of the literature on anti-VEGF agents and other angiogenesis inhibitors used in pre-clinical and clinical trials for cancer treatment.

Expert opinion: Future anti-angiogenic drug design centres on multiple protein targets and combinations including: growth factors, hypoxia-inducible factor and tumour endothelial cell markers unique to the tumour vasculature. Furthermore, treatment dosing, scheduling and combination with radiation and chemotherapy require further investigation, as does the potential of treating early disease, and the development of biomarkers which accurately predict response to therapy. These are essential for the future development of these drugs with individualised therapy likely to be the ultimate goal.     

Tumor vasculature directed drug targeting: applying new technologies and knowledge to the development of clinically relevant therapies

Recognition of the dependence of solid tumor growth on the formation of new blood vessels has ignited an enormous research effort aimed at the development of new therapeutic strategies for cancer. Besides direct application of drugs inhibiting endothelial cell function during angiogenesis, tumor vasculature directed drug-targeting strategies have been investigated for this purpose. In animal models of disease, proof of principle regarding the potential of selective interference with tumor blood flow as a powerful tumor therapy has been generated to its full extent. The challenge for the coming years will be to develop these strategies into clinically applicable ones. New insights into the molecular mechanisms prevailing in the endothelium during angiogenesis and into the mechanism(s) of action of drugs with anti-angiogenic activities, as well as new techniques to identify useful tumor endothelium specific target epitopes have in recent years been exploited to meet this challenge. This review summarizes vasculature directed therapeutic strategies proven to be successful in pre-clinical models and new (drug targeting) technologies enabling the development of more effective therapeutics for the treatment of cancer.     

Emerging role of apelin as a therapeutic target in cancer: a patent review

Since tumors cannot grow or spread without forming new blood vessels, inhibiting angiogenesis is an excellent approach for the treatment of cancer. Further, inhibitors of angiogenesis have mild side effects since they act on endothelial cells, which eliminate the possibility of developing resistance or tolerance in tumor cells, unlike that seen with chemotherapy drugs. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab acts by preventing new blood vessel formation in solid tumors and is approved by FDA to treat colorectal, lung, breast, glioblastoma and kidney cancers. The registration of this drug and its ongoing success in the clinic has validated the targeting of angiogenesis as an important approach to the treatment of solid tumors. Apelin is a novel angiogenic factor and recent studies indicate that apelin promotes angiogenesis, lymphangiogenesis and tumor growth in vivo and the angiogenic potential of apelin is similar to that of VEGF. Also, apelin expression is upregulated and has been shown to be associated with clinical outcome in certain human cancers. Thus, inhibition of apelin activity might lead to a new class of anti-angiogenesis drugs which should be more efficacious than those currently on the market due to their ability to be both anti-angiogenic as well as anti-lymphangiogenic. There are very few patents on the angiogenic effects of apelin and this review article focuses on these patented claims related to inhibiting apelin signaling and sheds more light on how blocking apelin signaling might open doors to a new class of angiogenic inhibitors.     

Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid

BACKGROUND AND PURPOSE: Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti-angiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate. EXPERIMENTAL APPROACH: Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos. KEY RESULTS: Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser(78) phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H(2)S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity. CONCLUSIONS AND IMPLICATION: S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.