Current Drug Targets - Volume 11, Issue 7, 2010

As a group, hematological malignancies represent the fourth most common cancer accounting for a little less than 10% of all cancer diagnoses. Overall outcomes for patients with hematological malignancies have improved as a result of chemotherapy and radiotherapy, however the heterogeneous nature of the biological characteristics of hematological malignancies necessitates a diverse range of treatments strategies. Currently outcomes vary dramatically between the various hematological malignancies with childhood acute lymphoblastic leukemia and Hodgkin's lymphoma having 5-year survival rates in the vicinity of 90% [1, 2], while those for patients with multiple myeloma and adults with acute leukemias remain less than 50% [3, 4]. Novel approaches to treatment and the introduction of new agents are essential to improve outcomes for patients who do not obtain cures with the currently available therapeutic options. A variety of approaches are likely to be needed for this diverse group of diseases. This special edition of Current Drug Targets focuses on new and emerging drug targets for the treatment of hematological malignancies with an emphasis on the diversity of therapeutic strategies. The first therapeutic agents for the treatment of malignancies were taken directly from the environment, with subsequent structural modifications often enhancing the utility of these agents. Such empirical treatments have played a major role in the management of hematological malignancies over the last few decades and include agents such as vincristine and etoposide. The introduction of high throughput screens has enabled new agents that impact on the growth and survival of malignant cells to be identified from among the multitude of chemically diverse compounds provided by nature. Lucas et al have reviewed the development of agents derived from higher plants for the treatment of leukemias and lymphomas and the rationale behind these developments, underpinning the enormous resource provided by naturally occurring compounds and the essential role they play in modern oncology. As our understanding of the biology of hematological malignancies has increased there has been a shift from empirical treatments to targeted therapies. Although it needs to be remembered that many empirically developed drugs do indeed hit specific targets in malignant cells. As the treatment of cancers with chemotherapeutic agents was pioneered in hematological malignancies so too targeted treatments are also having their greatest impact in this group of malignancies. Some of the outstanding additions over the last two decades are Rutuximab and Imatinib. Rutuximab, a humanised antibody to CD20, has dramatically improved the cure rate for patients with diffuse large B-cell lymphoma making it the most important single new agent for the treatment of B-cell lymphomas. As reviewed by Capietto et al in this issue, the success of this initial therapeutic antibody has been followed by a growing list of antibody-based therapies with a range of targets and mechanisms of action. There are now antibodies in clinical trial for the treatment of many hematological malignancies, and with an expanding list of these agent currently in clinical trial it appears these agents will play a significant role in future treatment strategies. Imatinib was the first agent specifically designed to directly target the protein product of an oncogene. It has revolutionized the treatment of chronic myeloid leukemia, the principal malignancy bearing the relevant genetic lesion. As with the development of Rutuximab, Imatinib has been followed by a plethora of targeted agents. The vast majority of these target enzymes that are constitutively activated in malignant cells, providing survival and proliferative advantages. Unlike CML, most hematological malignancies lack dominant cytogenetic abnormalities and so do not have such clearly defined targets. However, a number of inhibitors of cell signaling pathways that support malignant cell proliferation and survival are in clinical trial, including inhibitors of the PI-3K/AKT/mTOR and NF-κB pathways. In addition a number of agents that directly target the apoptotic machinery are being investigated with varying degrees of success and are reviewed here by Saborit-Villarroya et al. One of the more promising emerging target is the receptor tyrosine kinase Flt-3, the over activation of which is present in more that 30% of AML patients and is associated with a poor prognosis [5]. An agent that counters the actions of aberrant Flt-3 signaling has the potential to dramatically improve outcomes for this subset of AML patients and Pratz and Levis have reviewed the development of such agents and their progress towards the clinic. Over recent years there has been increasing interest in disrupting the microenvironment to enhance the efficacy of chemotherapeutic agents. These have included strategies for mobilizing malignant hematopoietic cells out of their protective bone marrow environment with agents such as chemokine inhibitors [6]. Other approaches include altering the behavior of the cells within the micro-environment. Perhaps one of the more developed is the use of inhibitors of p38MAPK, reviewed by Gaundar and Bendall. This strategy is of particular interest to multiple myeloma where the understanding of stromal/malignant cell interactions is well more mature and appreciated....

Programmed cell death, commonly associated with the term apoptosis, is an integrated intracellular program that plays a critical role in lymphoid tissue homeostasis. Alterations in this highly regulated process is a common feature of most lymphoid malignancies, thus facilitating tumor escape from traditional chemotherapeutic agents whose main endpoint is the induction of tumor cell death. In the last years, enormous progress has been made in understanding the deregulated signals that could lead to ineffective apoptosis in B lymphoid tumors. Consequently, several new strategies have been designed to modulate the key molecules of life-and-death decisions. Numerous novel approaches are being validated and some of them have progressed to clinical testing or have even been approved in a record time. In this review we will focus on current therapies that have demonstrated to trigger efficiently cell death in B lymphoid neoplasms, either by directly targeting the intracellular apoptotic machinery or by modulating different factors involved in its regulation.

FMS-Like-Tyrosine kinase-3 (FLT3) mutations are found in about 30% of cases of acute myeloid leukemia and confer an increased relapse rate and reduced overall survival. Targeting this tyrosine kinase by direction inhibition is the focus of both preclinical and clinical research in AML. Several molecules in clinical development inhibit FLT3, but thus far clinical responses have been limited. Correlative studies from monotherapy trials have established that responses require sustained, effective FLT3 inhibition in vivo. Studies combining FLT3 inhibitors with chemotherapy have demonstrated increased remission rates to date but have yet to produce a survival advantage. Currently the only approved FLT3 inhibitor available for off-label use is sorafenib, which clearly has clinical activity but does not commonly lead to a complete response. Several FLT3 inhibitors are currently being tested as single agents and in combination with chemotherapy, and it seems likely that a clinically useful drug will eventually emerge.

The development of therapeutic monoclonal antibodies (mAbs) has revolutionized the treatment of cancer along the last ten years. The best examples of their therapeutic efficacies have been obtained with rituximab for the treatment of CD20+ B-cell Non-Hodgkin Lymphoma (B-NHL), and several others antibodies with optimized bioactivities are now being developed for the treatment of various malignant hemopathies. We review here the main drugs developed in this field, and present some emerging concepts able to improve the bioactivities of the next generation of therapeutic mAbs.

MicroRNAs (miRNA) are small non-coding RNAs of ∼22 nucleotides that regulate the translation and stability of mRNA to control different functions of the cell. Misexpression of miRNA has been linked to disruption of normal cellular functions, which results in various disorders including cancers such as leukemias. MicroRNA involvement in disease has been the subject of much attention and is increasing our current understanding of disease biology. Such linkages have been determined by high-throughput studies, which provide a framework for characterizing differential miRNA expression levels correlating to different cytogenetic abnormalities and their corresponding malignancies. In addition, functional studies of particular miRNAs have begun to define the effects of miRNA on predicted mRNA targets. It is clear that miRNAs can serve as molecular markers of leukemias and the hope is that they can also serve as new therapeutic targets. Studies are beginning to elucidate how to deliver therapeutic antagonists to attenuate overexpressed miRNAs and to replace underexpressed miRNAs. In this review, we: i) discuss the current understanding of miRNA function and expression in normal hematopoiesis, ii) provide examples of miRNAs that are misregulated in leukemias, and iii) evaluate the current status and potential future directions for the burgeoning field of antisense oligonucleotides and other therapeutic attempts to intervene in miRNA disregulation in leukemias.

Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heterogeneity and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive. Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy today are either natural products or derivatives of natural products. The e l,normous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with biologic activity. This review will describe the investigation and application of natural products derived from higher plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plantderived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia.

The classical role of p38MAPK involves the transmission of death signals from stress stimuli such as ionizing radiation, inflammation and chemotherapy in normal and malignant cells. However emerging evidence points to having pleiotropic functions, ranging from cellular proliferation and survival, to cell cycle arrest and regulation of the tumor microenviroment. The mechanisms responsible for these diverse and rather contradictory functions of p38MAPK are only now being unraveled. In some hematological malignancies, p38MAPK is constitutively activated. The reasons for this are not fully understood, but can result from underlying genetic lesions such as the bcr/abl translocation. The involvement of p38MAPK in mediating cell cycle arrest in the face of cytotoxic damage suggests that p38MAPK may be a therapeutic target. The role of p38MAPK in cytokine production by the stromal compartment adds another level of complexity to the regulation of hematological malignancies that exhibit a degree of stromal dependence, at least some of which is cytokine driven. p38MAPK dependent cytokine production by malignant hematopoietic cells has also been observed, and promotes tumor cell adhesion, angiogenesis and osteoclastogenesis. This suggests a mutual relationship between tumor and stromal cells. In contrast, p38MAPK is required for the effects of cytotoxic agents in some hematological malignancies. These conflicting qualities point to the importance of careful consideration of the use of p38MAPK inhibitors as a therapeutic strategy.

Carcinoma of the biliary tree are rare tumors of the gastrointestinal tract with worldwide rising incidence for intrahepatic cholangiocarcinoma during the last years. Although complete surgical resection is the only curative approach, this can be accomplished in a minority of patients, since most of them present with advanced disease. In addition, those patients who have undergone complete surgical resection experience a high tumor recurrence rate. Non-resectable biliary tract cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy. It is therefore essential to search for new therapeutical approaches. After several years of preclinical research, the first clinical study data are now available for this tumor entity. Inhibitors of the epidermal growth factor receptor (EGFR) family, such as erlotinib, cetuximab, and lapatinib were recently investigated. Furthermore, bortezomib, an inbibitor of the proteasome, imatinib mesylate, an inhibitor of c-kit-R, bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), and sorafenib (BAY 43-9006), a multiple kinase inhibitor that blocks not only receptor tyrosine kinases but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway, were studied, as well. Although early evidence of antitumor activity was seen, the results are still preliminary and require further investigations.

The epidermal growth factor receptor (EGFR) and its ligands are frequently expressed in non-small-cell lung cancer (NSCLC). The EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib have shown clinical activity in NSCLC. However, only a small subgroup of NSCLC patients respond to these agents, suggesting that patients' selection is critical for EGFR TKIs sensitivity. In this regard, several studies have tried to individuate prognostic and predictive factors that are associated with sensitivity or resistance to anti-EGFR agents. A strong correlation between activating mutations in the EGFR TK domain and response to erlotinib and gefitinib has been reported in different trials. However, patients without EGFR mutations might also benefit of treatment with these drugs by experiencing prolonged disease stabilization. No significant correlation between EGFR overexpression and response to treatment has been found, while controversial results have been reported regarding the association between EGFR gene amplification and clinical response to TKIs. Different mechanisms of resistance to EGFR TKIs have also been described. Mutations of KRAS, that occur in approximately 20% of NSCLC, are associated with reduced response to EGFR TKIs. The EGFR T790M mutation, that reduces the affinity of the EGFR to gefitinib and erlotinib, and MET gene amplification produce acquired resistance to anti-EGFR agents. Taken together, these findings suggest that several different molecular alterations regulate the sensitivity of NSCLC cells to EGFR TKIs, and that a comprehensive approach to this phenomenon is necessary for an appropriate selection of patients that should be treated with these drugs.

Lung cancer remains the leading cause of malignancy-related mortality world-wide, in both men and women, with over a million cases diagnosed yearly. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, and most patients are diagnosed with advanced disease. Although substantial progress has been made in the therapeutic options currently available for patients with advanced NSCLC, chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may safely and effectively be administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor receptor (VEGFR) plays an essential role in tumor angiogenesis and proliferation, and has been a major focus of basic research and drug development in the field of Oncology. Approaches targeting VEGFR include mainly small molecule inhibitors of VEGFR tyrosine kinase activity. Among these, vandetanib, due to early findings of its antitumor activity and a good toxicity profile, has been largely investigated in advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, and sunitinib are being tested in ongoing clinical trials which will further define their role in the management of NSCLC. Here we review the current results and give an overview of some of the future developments of the main anti-VEGFR drugs in the treatment of NSCLC patients.

Accelerated atherosclerosis is the leading cause of coronary heart disease and stroke, which could account for high mortality rates in patients with diabetes. Although several hyperglycemia-elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of cardiovascular disease (CVD) in diabetes, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the phenomenon 'metabolic memory' and 'legacy effect', that is, vascular stresses during the diabetic exposure have persisted after glucose normalization. Further, there is a growing body of evidence that a receptor for AGEs (RAGE) is involved in signal transduction of AGEs in a variety of cells. In this paper, we review the role of the AGE-RAGE system in accelerated atherosclerosis, especially focusing on smooth muscle cell pathophysiology, and also discuss the possibility that the AGE/RAGE axis could be a potential therapeutic target for prevention of CVD in patients with diabetes.

Evidence from experimental and genetic studies suggest the existence of a potential link between the leukotrienes (LT) signalling cascade, and the pathogenesis/progression of atherosclerosis and its serious consequences such as acute myocardial infarction (AMI), stroke, aortic aneurysms, and intimal hyperplasia. LT biosynthetic enzymes are expressed within atherosclerotic lesion, leading to production of cysteinyl-leukotrienes (Cys- LTs) and LTB4 that exert potent pro-inflammatory action through interaction with CysLT and BLT receptor subtypes expressed on inflammatory and structural cells within the vascular wall. Genetic variants in the genes of the 5-LO pathway have been associated with the risk of developing AMI and stroke. As a result, anti-LT have recently received renewed interest for the treatment of atherosclerosis and its ischemic complications. The aim of this short review is to summarize our current understanding of the role of LTs and their receptors in the genesis and progression of atherosclerosis and review the recent developments on the use of antagonists.

Losing one of our main sensory systems such as hearing can have devastating consequences in the way we interact with the world. The main problem lies in the fact that the critical sensory cells, the auditory neurons and hair cells located in the cochlea are only generated during development and, when damaged, cannot be replaced. The options currently available to treat this condition are very limited, and are mostly represented by prosthetic devices such as hearing aids and cochlear implants. There is a clear need for a therapeutic breakthrough that will help the millions of people affected, and the advances in stem cell technologies are offering a glimmer of hope for this affliction. Although still at a very early stage, a growing bulk of literature is being produced attempting to pave the path for a stem cell-based therapy for deafness. From the many variables to bear in mind when developing this approach, two appear to be of paramount importance. First, different cell types are potentially to be used, all of them having advantages and disadvantages. Second, in order to target such a small and secluded organ as the cochlea, difficult surgical techniques are to be used, some of which still need to be developed. The present article will aim to present the most recent advances of the field, focussing on these two critical issues.