Current Cancer Drug Targets - Volume 11, Issue 9, 2011

It has been generally accepted that angiogenesis is involved in the pathogenesis of hematological malignancies, like acute and chronic leukemia, lymphoma, myelodysplastic syndromes, myeloproliferative neoplasms, and multiple myeloma. The extent of angiogenesis in the bone marrrow has been correlated with disease burden, prognosis, and treatment outcome [1]. Reciprocal positive and negative interactions between tumor cells and bone marrow stromal cells, namely hematopoietic stem cells, fibroblasts, osteoblasts/osteoclasts, endothelial cells, endothelial progenitor cells, T cells, macrophages and mast cells, mediated by an array of cytokines, receptors and adhesion molecules, modulate the angiogenic response in hematological tumors [2]. More recently, it has been emphasized the pro-angiogenic role of the so called “vascular niche”, indicating a site rich in blood vessels where endothelial cells and mural cells such as pericytes and smooth muscle cells create a microenvironment that affects the behavior of several stem and progenitor cells, in hematological malignancies [3]. The pivotal role of autocrine vascular endothelial growth factor (VEGF) loops in hematological malignancies has been confirmed by the coexpression of both VEGF and VEGF receptors (VEGFRs) in leukemia, lymphoma, and multiple myeloma coupled with direct effects on tumor cell survival, migration, and proliferation [4]. Antiangiogenesis was proposed as a cancer therapy over 30 years ago, when J. Folkman published in the New England Journal of Medicine a hypothesis that tumor growth is angiogenesis-dependent [5]. He hypothesized that tumors would be unable to grow beyond a microscopic size of 1 to 2 mm3 without continuous recruitment of new capillary blood vessels and introduced the concept that tumors probably secreted diffusible molecules that could stimulate the growth of new blood vessels toward the tumor and that the resulting tumor neovascularization could conceivably be prevented or interrupted by drugs called angiogenesis inhibitors [5]. Few angiogenesis inhibitors would ever be found before 1980, when the biopharmaceutical industry began exploiting the field of antiangiogenesis for creating new therapeutic compounds for modulating new blood vessel growth in angiogenesisdependent diseases until February 2004, when the US Food and Drug Administration (FDA) approved bevacizumab, a humanized anti-VEGF-A monoclonal antibody for the treatment of metastatic colorectal cancer in combination with 5- fluorouracil (FU)-based chemotherapy regimens [6]. A plethora of new antiangiogenic treatment approaches for patients affected by hematological tumors has emerged in recent years. Antiangiogenic therapies are mostly based on inhibiting the binding of VEGF to VEGFRs by neutralizing antibodies to the ligand or to the receptor, soluble receptors, small molecule inhibitors or are directed against the tyrosine kinase activity of the VEGFRs. Angiogenesis inhibitors can act as a two edged sword, because although they inhibit angiogenesis, they may also induce tumor re-growth and favour metastatic process [7]. In particular, the responses to antiangiogenic agents targeting VEGF are commonly transient, suggesting that there are effective escape mechanisms for blood vessel formation, and for this reason it has been suggested that anti-VEGF therapy is most effective when combined with chemotherapy or radiotherapy [8]. When chemotherapy is used in a conventional manner (i.e. bolus drug administration followed by a 3-4 week drug-free period to allow the host to recover from adverse side effects), the vascular damage is rapidly repaired during the recovery period. Browder et al. [9] showed that by shortening the drug-free break period, the antiangiogenic effect of cytotoxic drugs can be augmented, and this form of antiangiogenic chemotherapy, referred as metronomic chemotherapy [10], is more potent when combined with drugs that interfere with the endothelial cell survival activity of VEGF [11]. There is emerging evidence that VEGF-A may be replaced by other angiogenic pathways as the disease progress: higher amounts of fibroblast growth factor-2 (FGF-2) were detected when the VEGF pathway was blocked in mice [12] and an analysis of human breast cancer biopsies revealed that late stage breast cancers expressed a plethora of pro-angiogenic factors in contrast to earlier stage lesions, which preferentially expressed VEGF [13]. Another mechanism that can circumvent the antiangiogenic therapy is the recruitment of bone marrow-derived hematopoietic progenitor cells (HPC) and endothelial progenitor cells (EPC), both of which can obviate the necessity of VEGF signaling and can stimulate vasculogenesis in tumors [14-16]. Finally, anti-VEGF-VEGFRs therapies cause a number of side effects and the toxicities imply that angiogenesis is a multi-factorial biological process that involves various pathways in the body, such as the coagulation cascade, the immune system and blood flow regulation......

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.

Research on the formation of new blood vessels (angiogenesis) in general and vascular endothelial growth factor (VEGF) in particular is a major focus in biomedicine and has led to the clinical approval of the monoclonal anti- VEGF antibody bevazicumab; and the second-generation multitargeted receptor kinase inhibitors (RTKIs) sorafenib, sunitinib, and pazopanib. Although these agents show significant preclinical and clinical anti-cancer activity, they prolong overall survival of cancer patients for only months, followed by a restoration of tumor growth and progression. Therefore, there is a clear need to increase our understanding of tumor angiogenesis and the development of resistance. In this review we discuss up-to-date knowledge on mechanisms of tumor angiogenesis, and summarize preclinical and clinical data on existing and potential future anti-angiogenic agents and treatment strategies for Multiple Myeloma (MM) and other hematologic and solid malignancies.

Bone marrow microenvironment has been shown to play a crucial role in supporting the pathogenesis and the progression of several B-cell malignancies, including Waldenstrom's Macroglobulinemia (WM). Among the different cell types within the bone marrow milieu, endothelial cells have been proven to support WM cells growth. Based on the understanding of bone marrow neo-angiogenesis in plasma cell dyscrasias, a number of anti-angiogenic molecules are now available for the treatment of these diseases. Indeed, anti-angiogenic drugs, such as proteasome-, proteins kinase-C (PKC)-, phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR)-, and histone deacetylase (HDAC)- inhibitors are now available, playing a key role in the treatment of WM both in the preclinical settings and as part of clinical trials.

The tumor microenvironment is critical in the initiation and progression of cancerous growth, which is dependent on the establishment of a functional vascular network supporting neoplastic proliferation. While the precise role of tumor angiogenesis in lymphoma pathogenesis remains under active investigation, emerging data on the proangiogenic properties of the neoplastic lymphoma cells and mechanism of vascular assembly suggest that angiogenesis is highly relevant to the biology and therapy of non-Hodgkin's lymphoma. Antiangiogenic therapies in non-Hodgkin's lymphoma are in various stages of clinical development aiming at distinct angiogenic pathways operative in endothelial cells and perivascular stromal cells. The major classes of available antiangiogenics include anti-VEGF, small molecule inhibitors targeting proangiogenic receptor tyrosine kinases and their downstream signal transduction pathways, as well as immunomodulatory compounds with antiangiogenic properties. Preliminary clinical data indicate therapeutic advantages associated with strategies targeting dual compartments of vascular cells and tumor cells, as well as multiple angiogenic pathways within the tumor microenvironment. This review summarizes recent applications of antiangiogenic strategies in non-Hodgkin's lymphoma based on current understanding of the biology of lymphoma angiogenesis.

One of the best examples of the bench-to-bedside paradigm in recent years could be the myelodysplastic syndromes (MDS). New insight into the pathophysiology of this heterogeneous group of diseases has led to relevant clinical changes. We have now the World Health Organization classification of MDS, the International Prognostic Score System to evaluate risk according to some clinical and laboratory parameters, and the approval by most of the regulatory agencies around the world of 5-azacitidine, decitabine and lenalidomide to treat MDS patients. In the last decade a robust body of evidence supports the importance of angiogenesis and angiogenesis related molecules as having a key role in the pathophysiology of hematologic malignancies including of MDS. A group of researchers around the globe is testing drugs with angiogenesis-regulatory characteristics with some success. Experience from those trials has shown angiogenesis in MDS as a dynamic process, a “moving target”. Lenalidomide hit one and, although experience is being gained the complete answer is not there yet. Combinations of drugs with different mechanisms of actions are options that need to be tested. Herein we present some of the accumulated experience with these novel antiangiogenic-drugs.

The pathological role of bone marrow angiogenesis in human leukemias has been clearly established. Bone marrow neoangiogenesis is mediated by several growth factors, such as VEGF-A, VEGF-C, angiopoietin-1 and -2, FGF, HGF, TGF-β and others secreted by leukemic cells. The prognostic relevance of microvessel density, and expression of VEGF-A and -C has been demonstrated especially in acute myeloid leukemia. In the last years, several classes of angiogenesis inhibitors have been developed blocking several angiogenic pathways. These include drugs that inhibit the VEGF (with or without blockade of FLT3) and the mTor signalling cascade. Besides, thalidomide and lenalidomide although possessing a pleiotrophic mode of action including antiangiogenic properities have been evaluated in the treatment of human leukemias. In the current review we analyze the results of clinical trials employing these antiangiogenic drugs. Since the clinical efficacy of these compounds used as monotherapy is often limited, confined to certain subgroups of patients and frequently short lived, several trials combining standard chemotherapy with these agents have been initiated in order to demonstrate an additional benefit to standard therapy. Furthermore the introduction of new antiangiogenic drugs such as inhibitors of the angiopoietin and HGF/cMET pathway is on the horizon. Utilizing cocktails of inhibitors of several angiogenic pathways may represent a new possibility to augment the efficacy of antiangiogenic therapy in the future.

Lung cancer is the leading cause of cancer death. Conventional photodynamic therapy (PDT) using a nontargeted photosensitizer (ntPDT) is a treatment option for central- and peripheral-type early-stage lung cancer. However, ntPDT can cause severe side effects for normal tissue due to its non-selective distribution. To improve the selectivity and effectiveness of ntPDT for human lung cancer, we hypothesized that tissue factor would be a common yet specific biomarker and a potential therapeutic target for both lung cancer cells and lung tumor vascular endothelial cells in factor VII-targeted PDT (fVII-tPDT), which uses the fVII-Sn(IV) chlorin e6 conjugate for the treatment of human lung cancer. We first identified that tissue factor is indeed expressed on the human non-small cell lung cancer (NSCLC) lines A549 and H460 as well as on tumor vascular endothelial cells of A549 tumor xenografts from nude mice, but it is not expressed by vascular endothelial cells in healthy mouse organs including the lungs. We then demonstrated that fVII-targeting in fVII-tPDT significantly enhanced (up to 25-fold) the in vitro effect of ntPDT on the destruction of A549 and H460 lung cancer cells via the rapid induction of apoptosis and necrosis. We further demonstrated that in vivo administration of fVIItPDT significantly inhibited or eliminated subcutaneous A549 and H460 tumor xenografts in an athymic nude (ATN) mouse model without any obvious side effects. We conclude that fVII-tPDT is effective and safe for the treatment of human lung cancer in preclinical studies and that this methodology holds therapeutic potential for lung cancer patients.

Clarification of the molecular mechanisms of oncogenesis and drug resistance is a prerequisite for the development of new treatment strategies like molecularly targeted therapies. Recent studies demonstrate that EphA2 is overexpressed in human cancers and that EphA2 increases tumor invasion and survival. Thus, an EphA2 receptor antagonist, such as a specific tyrosine kinase inhibitor (in the form of an antibody, small molecule, peptide, or siRNA) or an antibody-drug conjugate that targets the EphA2 receptor could be the basis for a novel targeted antineoplastic therapy. This review summarizes the role of EphA2 in tumorigenesis and the development of EphA2 receptor antagonists as candidate anti-cancer agents. We suggests that continued research into the function of EphA2 signaling in the pathobiology of neoplasia could lead to more rationally designed therapeutics targeting EphA2 in solid tumors.

Hypermethylation of the Wnt inhibitory factor-1 (WIF-1) promoter has been implicated in the overactivation of the Wnt pathway in human lung cancer. Curcuminoids exert anti-cancer effects and have been reported to act as hypomethylating agents. Previously, we have investigated and compared the demethylation effects of three curcuminoids and observed that bisdemethoxycurcumin exhibited the strongest demethylation potency. In this study, we used lung cancer cell lines with WIF-1 promoter hypermethylated as a model to study the demethylating effect of bisdemethoxycurcumin on WIF-1 restoration, Wnt signaling activity and cell death. Bisdemethoxycurcumin directly suppressed the activity of DNA methyltransferase-1 (DNMT1) but did not influence DNMT1 expression. In addition, it induced WIF-1 promoter demethylation and protein re-expression. WIF-1 restoration in lung cancer cells down-regulated nuclear β-catenin and the canonical Wnt cascade. Furthermore, we also showed that down-regulation of Wnt signaling by WIF-1 was required for bisdemethoxycurcumin-induced apoptosis in certain lung cancer cell types. This report is the first to show that bisdemethoxycurcumin induces apoptosis by reactivating WIF-1 from a silenced state. Our results provide new insights into the anti-cancer actions of bisdemethoxycurcumin.

Edelfosine is an inhibitor of SK3 channel-mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-antimetastatic agent.