Current Medicinal Chemistry - Volume 19, Issue 7, 2012

This issue of “Current Medicinal Chemistry” focuses on the topic “Targeting Tumor Angiogenesis: an update”. Research on angiogenesis and anti-angiogenesis has been increasing in recent years. Angiogenesis is a process of new blood vessel formation from a pre-existing vascular bed and is regulated by a balance of pro- and anti-angiogenic factors. Angiogenesis occurs in organ development during embryogenesis and is a main pathway in tumor growth and progression. Interestingly, angiogenesis has been considered as a pharmacological target for tumor therapy. Antiangiogenic drugs have been developed to target pro-angiogenic factors, tyrosine kinase receptors driven angiogenesis, and de-regulated cellular pathways linked to angiogenesis and involved in tumor growth. The review papers presented in this issue of the journal summarize approaches that are currently focusing on the clinical application of angiogenesis inhibitors in several tumor types, and also provide a general overview of the mechanisms that could be important in angiogenesis and as a novel pharmacological target. Prof. Ribatti and co-workers present an overview of inflammatory processes in tumor angiogenesis, with particular regard to microenvironments. In this context several strategies targeting inflammatory angiogenesis have been discussed. My co-workers and I review angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase cascade in the development of hepatocellular carcinoma. The development of sorafenib, which targets this pathway, has been discussed from its discovery through to clinical development, as have ongoing trials on the combination between sorafenib and trans-arterial chemoembolization in hepatocellular patients. Dr. Guarini and co-workers review Everolimus as a novel agent targeting the m-TOR pathway and angiogenesis in Hodgkin Lymphoma. The importance of m-TOR signaling in Hodgkin Lymphoma angiogenesis and development has been also discussed. Prof. Sciorsci and co-workers focus on Gonadotropin Releasing Hormone, its receptor and Gonadotropin Releasing Hormone analogues that are currently employed as therapeutic agents in tumor patients. The role of Gonadotropin Releasing Hormone analogues as antiangiogenic drugs in a spontaneous breast cancer animal model and human breast cancer is discussed. Prof. De Sarro and co-workers present data about the use of Bevacizumab, a recombinant monoclonal antibody which binds Vascular Endothelial Growth Factor, in malignant gliomas and provide a summary of currently available data on efficacy and safety. Dr. Morabito and co-workers review Bevacizumab and its efficacy in addition to first-line chemotherapy in non-small-cell lung cancer with non-squamous histology. Results and future directions are discussed.

Angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAF kinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients.

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.

The immune system regulates angiogenesis in cancer by means of pro- and anti-angiogenesis activities. In fact, both innate (macrophages, granulocytes, mast cells, dendritic cells, natural killer cells, and platelets) and adaptive (T and B lymphocytes) immune cells synthesize several pro- and anti-angiogenic mediators. Moreover, in pre-clinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy. In this review article, we will focus on some angiogenenic and anti-angiogenic molecules properties of immune cells that may be utilized for a potential parmacological use as anti-angiogenic agents in cancer.

Bevacizumab is a monoclonal antibody directed against Vascular Endothelial Growth Factor (VEGF). Evidence about its efficacy in addition to first-line chemotherapy in non-small-cell-lung-cancer (NSCLC) has been produced by two large randomized phase III clinical trials (ECOG 4599 and AVAiL), conducted in a clinically selected population with non-squamous histology and without major risk factors for bleeding. In the ECOG 4599 trial, the addition of bevacizumab (15 mg/kg) to carboplatin plus paclitaxel produced a statistically significant and clinically relevant improvement in overall survival (OS), that was the primary endpoint of the trial (12.3 months vs 10.3 months, HR 0.79; p=0.003). Furthermore, patients receiving bevacizumab showed a significant improvement in progression-free survival (PFS) and in objective response rates. Treatment with bevacizumab was well tolerated by the majority of patients, but was still associated with increased risk of clinically significant bleeding (4.4% vs 0.7%, p=0.001). In the AVAiL trial the addition of bevacizumab (at the dose of 7.5 and 15 mg/kg) to cisplatin plus gemcitabine produced a small improvement in PFS, but no differences in OS. Information from retrospective analysis and two large observational studies (SAIL and ARIES) have confirmed the safety profile of first-line bevacizumab with a wide range of chemotherapy partners, but whether its efficacy is comparable when combined with the different regimens is still unknown. The identification of predictive factors of efficacy would be relevant for the optimal use of the drug, but to date we have no conclusive data in this direction.

Glioblastoma multiforme (GBM) is a common and malignant primary brain tumor arising from glial precursors the survival of which is estimated to be about 14 months after diagnosis despite current standard care with radiotherapy, surgery, and chemotherapies. Therapeutic approaches were greatly improved in the last years; however, GBM still represents the most lethal subtype of glioma. Actually, it has been estimated that only about 3.4% of patients will survive at the most five years when obtaining the best outcome from treatment; however, this depends on tumor resistance, which is generally related to repairing radiation injury, and self- improving cell growth repair and survival. All GBMs recur after initial therapy, limiting patients’ survival at 20-25% within 1 year after diagnosis of recurrent disease. Moreover, for recurrent GBM response rates are less than 10% (ranging from 5% to 9%), and progression free survival at 6-month (PFS-6) rates ranges between 9% and 28% (median 15%). The development of targeted therapy based on tumor vascular blockade led to the approval of bevacizumab for recurrent or progressive glioblastoma, since it was proven that this offers a new opportunity for patients suffering from this malignancy. Bevacizumab is a recombinant antivascular monoclonal antibody binding to circulating Vascular Endothelial Growth Factor (VEGF) preventing this cytokine from reaching its receptors (VEGFR1 and VEGFR2) on endothelium, resulting in an inhibition of cells proliferation and vessels sprouting. The aim of this review is to address bevacizumab mode of action in malignant gliomas and provide a summary on currently available data on efficacy and safety.

The Gonadotropin-Releasing Hormone (GnRH) exists in two isoforms, GnRH-I and GnRH-II, in most vertebrates, including humans. Both of these isoforms and their respective receptors have been found in many healthy and pathologic extra nervous system tissues, such as cells found in cancers of the reproductive systems and, in particular, in breast cancer. GnRH analogues are used as therapeutic agents in the case of sex-hormone-dependent tumours. Besides acting as suppressors of steroidogenesis, GnRH analogues seem to interfere with mitogenic signal transduction pathways, thus behaving as negative regulators of tumour growth and progression. GnRH analogues counteract the proliferating effects of both epidermal growth factor (EGF) and insulin like growth factor (IGF-I); additionally, it affects the mitogen-activated protein kinase (MAPK) cascade and modulates the activity of the urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitory (PAI) system, which is involved in the process of metastasis. In addition, GnRH analogues decrease the expression of many growth factors involved in the development of human uterine myomas (as well as endometriotic tissue), such as the vascular endothelial growth factor (VEGF), which is deeply implied in the angiogenesis of many benign and malignant tumours, including breast cancer. Angiogenesis is one of the primary processes leading to the progression and metastasis of breast cancer cells, and a key therapeutic goal in the fight against tumours is the blocking of new vessel sprouts. Given these premises, this review provides an update on the background of anti-neoplastic properties of GnRH analogues..

DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a type II C-type lectin that functions as an adhesion molecule located on dendritic cells (DCs). It enables some of the functions of DCs, including migration, pathogen recognition, internalisation and processing, and their binding to T cells. HIV-1 has been reported to enter DCs by being bound to DC-SIGN, escaping the normal lytic pathway in DCs' endosomes and avoiding the immune system defence system. A very similar mechanism of survival has been observed for some other pathogens. This makes DC-SIGN a receptor of interest in the design of distinctive anti-infectives that would inhibit DC-SIGN-pathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DC-SIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DCSIGN binds mannose- and fucose-based oligo- and polysaccharides, their structural mimics have been designed and proved to inhibit pathogen-DC-SIGN interaction. Furthermore, recent in vitro studies have demonstrated that DC-SIGN antagonists block effectively the transmission of pathogens like HIV-1 and Ebola to CD4+ T cells. Although DC-SIGN has not been validated in vivo as a druggable target yet, we await future DC-SIGN antagonists as a new and highly promising group of novel anti-infectives.

Frontotemporal Lobar Degeneration (FTLD) is characterized by behavioral changes, executive dysfunctions, and language impairment, sustained by different neuropathological patterns. The collective efforts of clinical, pathological and genetic studies have recently opened new insights into the underpinnings of pathological mechanisms of this complex disorder. Different types of inclusions define the new conceptual framework for FTLD classification. Up to now, Tau (FTLDTau-positive), TAR DNA-binding protein (TDP43, FTLD Tau-negative TDP43-positive) have been recognized as the most frequent neuropathological hallmarks of FTLD. In some clinical cases, monogenic forms are identified, mainly due to Microtubule Associated Protein (MAPT) or Granulin (GRN) mutations. No treatments for FTLD are available yet, and off-label medications studies testing potential modifying treatments on the basis of neuropathological positive, inhibitors of Tau kinases or manipulation of Tau-processing haploinsuffciency associated with GRN mutations, has been counteracted into pathological processing of TDP-43 and other key-molecules involved and their consequent translocation from nucleus to cytoplasm, and growing number of potential therapeutic targets. In this continuously new findings on molecular targets and modifying therapies in FTLD.

Methionine aminopeptidases (MetAPs), which remove methionine residue from newly synthesized polypeptide chains, are a class of metalloproteases ubiquitously distributed in both eukaryotes and prokaryotes. MetAP-2 inhibition can induce G1 cell cycle arrest, cytostasis in tumor cells in vitro and inhibition of tumor growth in vivo. The discovery of fumagillin with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. Early drug discovery efforts have focused on analogs of fumagillin, which irreversibly inhibit MetAP-2 through covalent modification of an epoxide. Several fumagillin analogs, like CKD-732, TNP-470 and PPI-2458, were found to be potent selective inhibitors of MetAP-2 (proteolytic activity) and endothelial cell proliferation. Further, they have entered in clinical trials for the treatment of different types of tumors. Recently, attention has been paid to reversible human MetAP-2 inhibitors, such as bengamides, 2-hydroxy-3-aminoamides, anthranilic acid sulfonamides and triazole analogs, which have demonstrated their potential to inhibit angiogenesis and tumor growth in vivo as well. This review article mainly discussed the development of MetAP-2 inhibitors in cancer therapy and also summarized their structure-activity relationships.

Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.

Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.

Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is a deoxycytidine nucleoside analogue of deoxycytidine in which two fluorine atoms have been inserted into the deoxyribose ring. Like other nucleoside analogues, gemcitabine is a prodrug. It is inactive in its original form, and depends on the intracellular machinery to gain pharmacological activity. What makes gemcitabine different from other nucleoside analogues is that it is actively transported across the cell membrane, it is phosphorylated more efficiently and it is eliminated at a slower rate. These differences, together with self-potentiation mechanisms, masked DNA chain termination and extensive inhibitory efficiency against several enzymes, are the source of gemcitabine's cytotoxic activity against a wide variety of tumors. This unique combination of metabolic properties and mechanistic characteristics is only found in very few other anticancer drugs, and both the FDA and the EMEA have already approved its use for clinical purposes, for the treatment of several types of tumors. In spite of the promising results associated with gemcitabine, the knowledge of its mode of action and of the enzymes it interacts with is still not fully documented. In this article we propose to review all these aspects and summarize the path of gemcitabine inside the cell.