Vascular disrupting agents

It has been well established that a functioning vascular supply is essential for solid tumor growth and metastases. In the absence of a viable vascular network, tumors are unable to grow beyond a few millimeters and therefore remain dormant. Initiation of angiogenesis allows for continued tumor growth and progression. Targeting tumor vasculature, either by inhibiting growth of new tumor blood vessels (antiangiogenic agents) or by destroying the already present tumor vessels (vascular disrupting agents; VDA), is an area of extensive research in the development of new antitumor agents. These two groups differ in their direct physiological target, the type or extent of disease that is likely to be susceptible, and the treatment schedule. VDAs target the established tumor blood vessels, resulting in tumor ischemia and necrosis. These agents show more immediate effects compared to antiangiogenic agents and may have more efficacy against advanced bulky disease. VDAs can be divided into two groups--ligand-bound and small molecule agents. Both VDA groups have demonstrated antitumor effects and tumor core necrosis, but consistently leave a thin rim of viable tumor cells at the periphery of the tumor. More evidence suggests VDAs will have their greatest effect in combination with conventional chemotherapy or other modes of treatment that attack this outer rim of cells.     

Vascular disrupting agents

A clear definition for vascular targeting agents (VTAs) and vascular disrupting agents (VDAs) has separated the two as distinct methods of cancer treatment. VDAs differ from VTAs (antiangiogenesis drugs) in their mechanism of action. VTAs attempt to keep new blood vessels from forming and do not act on blood vessels that already feed existing tumors. In contrast, VDAs cause the vascular structure inside a solid tumor to collapse, depriving the tumor of blood and oxygen it needs to survive. Therefore, VDAs are an attractive way to approach the cancer problem by combating developed tumors. The following review discusses six small molecule VDAs, namely DMXAA, ZD6126, TZT1027, CA4P, AVE8062, and Oxi4503, their synthesis, biological mechanism of action, and current clinical status.     

Tumor vasculature as a therapeutic target in non-small cell lung cancer

Despite developments in conventional (chemo)radiotherapy and surgery, survival of non-small cell lung cancer (NSCLC) patients remains poor. Treatments with targeted molecular drugs offer novel therapeutic strategies. Bevacizumab, a recombinant anti-vascular endothelial growth factor (VEGF) antibody, is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC. However, a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain. Furthermore, novel agents targeting the pre-existing NSCLC vasculature (i.e. vascular disrupting agents, VDAs) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies. Herein, we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC.     

Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after cessation of treatment. In numerous preclinical studies, angiogenesis inhibitors were shown to be efficient in the treatment of many pathological conditions, including solid cancers. In most clinical trials, however, this approach turned out to have no significant effect, especially if applied as monotherapy. Recovery of tumors after therapy is a major problem in the management of cancer patients. The mechanisms underlying tumor recovery (or therapy resistance) have not yet been explicitly elucidated. This review deals with the transient switch from sprouting to intussusceptive angiogenesis, which may be an adaptive response of tumor vasculature to cancer therapy that allows the vasculature to maintain its functional properties. Potential candidates for molecular targeting of this angioadaptive mechanism are yet to be elucidated in order to improve the currently poor efficacy of contemporary antiangiogenic therapies.     

Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12

Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12–CXCR4 axis have emerged as additional or alternative agents for neo-adjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of “selective blockade” of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression.     

The role of cytokines in oncology

The availability of sufficient quantities of recombinant human cytokines and promising preclinical data have led to their introduction into clinical trials. Cytokines have potential as new therapeutic agents in a variety of hematological disorders as well as in solid tumors. Only a few of the still increasing number of these glycoprotein hormones have been studied in humans so far, either as single agents or in combination with chemotherapy and other cytokines. Their clinical effects, beneficial role in supportive care, and use in the treatment of certain cancer patients are reviewed.     

Vascular-homing peptides for targeted drug delivery and molecular imaging: Meeting the clinical challenges

The vasculature of each organ expresses distinct molecular signatures critically influenced by the pathological status. The heterogeneous profile of the vascular beds has been successfully unveiled by the in vivo phage display, a high-throughput tool for mapping normal, diseased, and tumor vasculature. Specific challenges of this growing field are targeted therapies against cancer and cardiovascular diseases, as well as novel bioimaging diagnostic tools. Tumor vasculature-homing peptides have been extensively evaluated in several preclinical and clinical studies both as targeted-therapy and diagnosis. To date, results from several Phase I and II trials have been reported and many other trials are currently ongoing or recruiting patients. In this review, advances in the identification of novel peptide ligands and their corresponding receptors on tumor endothelium through the in vivo phage display technology are discussed. Emphasis is given to recent findings in the clinical setting of vascular-homing peptides selected by in vivo phage display for the treatment of advanced malignancies and their altered vascular beds.     

Novel technologies for antiangiogenic drug delivery in the brain

Antiangiogenic therapies aimed at inhibiting the formation of tumor vasculature hold great promise for cancer therapy, with multiple compounds currently undergoing clinical trials. As with many forms of chemotherapy, antiangiogenic drugs face numerous hurdles in their translation to clinical use. Many such promising agents exhibit a short half-life, low solubility, poor bioavailability and multiple toxic side effects. Furthermore, when targeting malignant brain tumors the blood-brain barrier represents a formidable obstacle, preventing drugs from penetrating into the central nervous system (CNS). In this review, we discuss several preclinical antiangiogenic therapies and describe issues related to the unique conditions in the brain with regard to cancer treatment and neurotoxicity. We focus on the limitations of antiangiogenic drugs in the brain, along with numerous solutions that involve novel biomaterials and nanotechnological approaches. We also discuss an example in which modifying the properties of an antiangiogenic compound enhanced its clinical efficacy in treating tumors while simultaneously mitigating undesirable neurological side-effects.Key words: angiogenesis, CNS, glioma, drug-delivery, brain, blood-brain-barrier, nanoparticles, lodamin     

Antibody drug-conjugates targeting the tumor vasculature: Current and future developments

Reducing the blood supply of tumors is one modality to combat cancer. Monoclonal antibodies are now established as a key therapeutic approach for a range of diseases. Owing to the ability of antibodies to selectively target endothelial cells within the tumor vasculature, vascular targeting programs have become a mainstay in oncology drug development. However, the antitumor activity of single agent administration of conventional anti-angiogenic compounds is limited and the improvements in patient survival are most prominent in combinations with chemotherapy. Furthermore, prolonged treatment with conventional anti-angiogenic drugs is associated with toxicity and drug resistance. These circumstances provide a strong rationale for novel approaches to enhance the efficacy of mAbs targeting tumor vasculature such as antibody-drug conjugates (ADCs). Here, we review trends in the development of ADCs targeting tumor vasculature with the aim of informing future research and development of this class of therapeutics.Key words: tumor, vasculature, immunotherapy, antibody-drug conjugates, monoclonal antibody, cancer, angiogenesis     

抑制血管生成治疗肿瘤的策略和展望

新生血管生成是绝大多数肿瘤得以生长和转移的必要前提。所以 ,通过抑制肿瘤血管生成来抑制肿瘤是非常有前途的一种方法 ,有望发展成为一种新型的癌症疗法。主要可以分为两大类 :一是通过抑制促血管生成信号或扩大抑制血管生成因子的作用来干扰肿瘤新生血管的形成过程 ,这领域的广泛研究已经发现了一系列促血管生成因子及其抑制剂和血管生成抑制因子 ;二是利用肿瘤血管与正常血管的差别来携带杀伤性药物直接特异性破坏已形成的肿瘤血管 ;另外 ,内皮细胞及其前体细胞制成疫苗也可起到直接杀伤作用。到目前为止 ,虽然很多抑制肿瘤血管的药物已经被用于临床试验 ,但结果往往不尽如人意 ,从长远来看 ,需要更有效的治疗方法。包括抗血管基因治疗策略 ,靶向药物导入系统的研究 ,以及抗血管生成药物和免疫疗法、化疗和放射治疗的联合应用都在探讨中。随着肿瘤模型评估系统的发展 ,抗血管治疗肿瘤的方法在不久的将来一定会广泛进入临床应用。     

Antibody drug-conjugates targeting the tumor vasculature

Reducing the blood supply of tumors is one modality to combat cancer. Monoclonal antibodies are now established as a key therapeutic approach for a range of diseases. Owing to the ability of antibodies to selectively target endothelial cells within the tumor vasculature, vascular targeting programs have become a mainstay in oncology drug development. However, the antitumor activity of single agent administration of conventional anti-angiogenic compounds is limited and the improvements in patient survival are most prominent in combinations with chemotherapy. Furthermore, prolonged treatment with conventional anti-angiogenic drugs is associated with toxicity and drug resistance. These circumstances provide a strong rationale for novel approaches to enhance the efficacy of mAbs targeting tumor vasculature such as antibody-drug conjugates (ADCs). Here, we review trends in the development of ADCs targeting tumor vasculature with the aim of informing future research and development of this class of therapeutics.     

Plocabulin,a novel tubulin inhibitor,has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors

The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin inhibitor, plocabulin, in patient-derived xenograft (PDX) models of GIST, a disease generally considered to be resistant to cytotoxic agents. Three PDX models of GIST with different KIT genotype were generated by implanting tumor fragments from patients directly into nude mice. We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. The efficacy of the drug was assessed by volumetric analysis of the tumors, histopathology, immunohistochemistry and Western blotting. Plocabulin treatment led to extensive necrosis in all three models and significant tumor shrinkage in two models. This histological response can be explained by the drug's vascular-disruptive properties, which resulted in a shutdown of tumor vasculature, reflected by a decreased total vascular area in the tumor tissue. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype.     

Tumor heterogeneity: morphological, molecular and clinical implications

Malignant tumors are characterized by their great heterogeneity and variability. There are hundreds of different types of malignant tumors that harbour many oncogenic alterations. The tumor heterogeneity has important morphological, molecular and clinical implications. Except for some hematopoietic and lymphoproliferative processes and small cell infant tumors, there are not specific molecular alterations for most human tumors. In this review we summarize the most important aspects of carcinogenesis and chemoradiosensitivity of malignant cells. In this regard, some oncogenes such as neu, ras and bcl-2 have been associated with cellular resistance to treatment with anticancer agents. The knowledge of oncogenic alterations involved in each tumor can be important to correlate the morphological features, the genetic background, the prognosis and the clinical response to treatment with anticancer agents. Based on the molecular background of the tumor there are new cancer gene therapy protocols. For example using adenovirus Ela in tumors with overexpression of neu oncogene, inhibitors of tyrosine kinase specific for the PDGF receptor in glioma, inhibitors of farnesil transferase to prevent ras activity in tumors with mutations in the ras gene.     

Angiogenesis and vascular growth factor receptor expression in malignant melanoma.

The growth and metastases of many solid tumors are dependent on the recruitment of new blood vessels. Tumor angiogenesis is most likely initiated by paracrine release of growth factors that bind to their corresponding endothelial cell surface receptors. To determine whether angiogenesis and growth factor receptor expression are consistent findings in malignant melanoma, primary human melanomas were examined for mRNA expression of receptors for fibroblast growth factors (FGFR-1, FGFR-2), vascular endothelial growth factor (VEGFR-1, VEGFR-2), and the receptors Tiel and Tie2. Charts were reviewed and archival formalin-fixed, paraffin-embedded primary tumors were obtained from patients with thin (<1 mm; n = 10), intermediate (1 to 4 mm; n = 10), or thick malignant melanoma (>4 mm; n = 8). Also examined was whether melanoma cell lines could induce endothelial growth factor receptor synthesis by metabolic labeling. It was found that tumor vascularity did not correlate with clinical stage, melanoma thickness, or clinical outcome. It was also found that melanoma cell lines were not capable of directly regulating endothelial cell synthesis of growth factor receptors. However, expression of Tiel and VEGFR-2 mRNA by the tumor vasculature in select stage IA-IIB patients, and FGFR-1 mRNA expression by the tumor cells in the same clinical stages was found. The expression of these growth factor receptors did not correlate with clinical outcome. These data suggest that angiogenesis is not a prominent characteristic of primary malignant melanoma lesions and that the endothelial cell expression of Tiel and VEGFR-2 in vivo is probably not directly induced by the tumor.     

肿瘤血管靶向药物的研究进展

肿瘤血管在实体瘤的发生发展中具有重要的作用,靶向肿瘤血管的新药研发已成为一个热点领域.抗肿瘤血管的治疗策略分为肿瘤新生血管生成抑制剂（tumor angiogenesis inhibitor,TAI）和肿瘤血管靶向药物（vascular targeting agents,VTAs）两方面的研究.肿瘤新生血管生成抑制剂旨在抑制肿瘤新生血管生成的过程,而肿瘤血管靶向药物则是通过快速而有选择性地破坏肿瘤血管功能,使肿瘤血供受阻,导致肿瘤坏死.VTA类药物分为两类：一是小分子抑制剂（small molecule agents）,利用肿瘤血管和正常组织血管存在的差别选择性地破坏肿瘤血管;另一种是生物制剂（biological agents）,借助能够特异结合肿瘤血管的配体将毒素、凝血诱导剂、凋亡诱导分子等运送到肿瘤血管,引起血管阻塞使肿瘤坏死.     

Molecular targeting of angiogenesis

The majority of pharmacological approaches for the treatment of solid tumors suffer from poor selectivity, thus limiting dose escalation (i.e., the doses of drug which are required to kill tumor cells cause unacceptable toxicities to normal tissues). The situation is made more dramatic by the fact that the majority of anticancer drugs accumulate preferentially in normal tissues rather than in neoplastic sites, due to the irregular vasculature and to the high interstitial pressure of solid tumors. One avenue towards the development of more efficacious and better tolerated anti-cancer drugs relies on the targeted delivery of therapeutic agents to the tumor environment, thus sparing normal tissues. Molecular markers which are selectively expressed in the stroma and in neo-vascular sites of aggressive solid tumors appear to be particularly suited for ligand-based tumor targeting strategies. Tumor blood vessels are accessible to agents coming from the bloodstream, and their occlusion may result in an avalanche of tumor cell death. Furthermore, endothelial cells and stromal cells are genetically more stable than tumor cells and can produce abundant markers, which are ideally suited for tumor targeting strategies. This review focuses on recent advances in the development of ligands for the selective targeting of tumor blood vessels and new blood vessels in other angiogenesis-related diseases.     

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.     

Antibody-based targeting of the tumor vasculature

Conventional cytotoxic therapies of cancer often suffer from a lack of specificity, leading to a poor therapeutic index and considerable toxicities to normal organs. An elegant way to overcome the disadvantages of conventional tumor therapy is the selective delivery of therapeutics to the tumor site by their conjugation to a carrier molecule specific for a tumor-associated molecular marker. Markers expressed on the tumor's vasculature represent particularly attractive targets for a site-specific pharmacodelivery due to their inherent accessibility for blood-borne agents and the various therapeutic options that they allow, ranging from intraluminal blood coagulation to the recruitment of immune cells. In this review, we will outline advances in the preclinical and clinical evaluation of antibody-based vascular targeting agents, describe technologies for the discovery of novel vascular targets and discuss future prospects for vascular targeting applications.