Current Pharmaceutical Design - Volume 18, Issue 23, 2012

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. Although initial genetic events are considered primarily responsible for the first step(s) of neoplastic transformation, the development and progression of the CLL clone are thought to be affected by various micro-environmental signals that regulate proliferation and survival of malignant B cells. In the present review, we focus on specific interactions of CLL cells with the microenvironmental component, as they occur through the usage by CLL cells of specific molecular structures whose expression has been associated with prognosis, including: i) interactions of CLL cells via the surface BCR and dependent on specific molecular features of the BCR itself and/or the presence of the BCR-associated molecule ZAP- 70; ii) non-BCR-dependent proliferative and/or pro-survival interactions of CLL cells by CD49d and CD38. An overview of the putative drugs that could be employed to target specific molecules involved in CLL cells/tumor microenvironment interactions is also proposed in the closing chapter of the review.

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults in the Western world and is characterized by the accumulation of monoclonal CD5+ mature B cells in the blood. The disease has a highly variable clinical course. CLL is subdivided into two disease subtypes, whereby leukemias with hypermutated immunoglobulin heavy chain variable (IGHV) genes have a more favorable prognosis than those with unmutated IGHV genes, which tend to show advanced, progressive disease, adverse cytogenetic features and resistance to therapy. The current view is that both CLL types derive from antigen-experienced cells. Based on the finding that the IGHV repertoire is highly restricted and biased, as compared to the normal adult B-cell repertoire, it has been hypothesized that CLL cells are selected by some sort of antigenic pressure. Hereby, either autoantigens or antigens derived from apoptotic cells or pathogens are essential to trigger CLL pathogenesis. Although different cytogenetic aberrations were shown to contribute to CLL leukemogenesis, it remains unclear which abnormalities are primary events. Very recently, whole-genome sequencing identified genes that are recurrently mutated and provided novel insights into the mechanisms of oncogenic transformation. Because of the impact on prognosis, it is important to unravel the role of antigenic selection in CLL. Interestingly, B cell receptor (BCR) signaling is aberrantly increased in CLL and expression of tyrosine kinase ZAP70, which is able to signal downstream of the BCR, is a prognostic indicator. In this context we discuss the functional significance of antigenic selection in CLL and describe emerging agents to target BCR signaling that are currently being tested as a novel therapeutic strategy for CLL.

Chemoimmunotherapy is the new gold standard of therapy for patients with advanced chronic lymphocytic leukemia (CLL). However, in spite of the high complete response rate achieved with chemoimmunotherapy, all patients eventually relapse and CLL is still incurable. Newer and more rationally developed compounds are clearly needed for these patients, in particular those with refractory disease. Among these agents, novel monoclonal antibodies, cyclin-dependent kinase inhibitors, chromokine receptor antagonists, lenalidomide, signal transduction inhibitors and pro-apoptotic molecules have recently shown some efficacy in patients with relapsed or refractory disease. Hopefully, the combined use of these agents in risk-adapted treatment strategies will improve the outcome of patients with CLL and set the stage for their cure.

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia, originates from an expansion of a rare population of CD5+CD19+ mature B-cells. CLL occurs in two forms, aggressive and indolent. For the most part aggressive CLL shows high ZAP-70 expression and unmutated IgH VH, while indolent CLL is characterized by low ZAP-70 expression and mutated IgH VH. Despite detailed studies of clinical features and chromosomal abnormalities in CLL, molecular details underlying disease development are still not entirely clear. In the past several years, more and more such mechanisms have emerged. Recent studies clarified mechanistic details of how activation of TCL1, a critical molecule in aggressive CLL, initiates this malignancy. In indolent CLL characterized by 13q14 deletions, MiR-15/16 targeting BCL2 and MCL1 and DLEU7 targeting TNF pathway were proposed as tumor suppressors. Analysis of CLL coding genome identified NOTCH1 as a frequent target of activating mutations. Interestingly most of these pathways have downstream activating effects on the NF-kB family transcription factors. Several mouse models of CLL, confirmed importance of these pathways in the pathogenesis of CLL. Here, we discuss what has been learned from these new pathways, and analyze how CLL mouse models confirm newly discovered molecular mechanisms of CLL.

Purine nucleoside analogues (PNA) are the cytotoxic agents highly active in the treatment of indolent lymphoid malignancies. These drugs have chemical structure similar to adenosine or deoxyadenosine. PNAs are characterized by a similar mechanism of cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. In addition, PNAs induce apoptosis which is the end-point of their action. Older PNAs, pentostatin (DCF; 2’- deoxycoformycin), cladribine (2-CdA; 2-chloro-2’-deoxyadenosine) and fludarabine (2-fluoro-9-(-D-arabinosyl)-adenine) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. In addition three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. This review summarizes current knowledge on the mechanism of action and pharmacokinetic properties of older and new PNAs. Clinical activity and toxicity of PNAs, especially in hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-V), prolymphocytic leukemia (PLL) and other rarer chronic lymphoid leukemias, are also presented. 2-CdA and DCF, introduced in the 1980s, changed radically the treatment modality, inducing complete and durable responses in the majority of patients with HCL. In contrast, the results of the treatment of HCL-V with PNA are rather poor. There are also several reports indicating activity of PNAs in PLL and large granular lymphocyte leukemia. Clofarabine, nelarabine and forodesine need further investigation in rarer lymphid leukemias, to better define their status in the treatment of these disorders.

A key feature of the clinical course of chronic lymphocytic leukemia (CLL) is that it induces a state of immunosuppression, causing increased susceptibility to infections and failure of anti-tumor immune responses. Cytotoxic chemotherapy still forms the mainstay of most current treatment regimens, but is not curative, and its lack of specificity means that it also targets normal immune cells, exacerbating this immunosuppression. This can result in effective treatments being limited by infectious complications, particularly in the elderly who comprise the majority of patients with this disease. Immunotherapy potentially offers a way out of this dilemma, due to its improved specificity and ability to enhance immune responses to both the tumor and infectious agents. There has been a dramatic increase in the range of available immunotherapeutic options over the past decade, and many are now in the process of making the transition to the clinic. This review will discuss both the immune defect in CLL, and emerging immunotherapies, including CD40 ligand gene therapy, lenalidomide, CLL vaccines, CXCR4 antagonists, and adoptive cellular immunotherapies such as chimeric antigen receptor modified T-cells.

Treatment of chronic lymphocytic leukemia (CLL) has recently undergone revolutionary changes. Two large randomized trials demonstrated superiority of chemoimmunotherapy combining fludarabine and cyclophosphamide with monoclonal anti-CD20 antibody rituximab (FCR) over fludarabine and cyclophosphamide (FC) alone in first line and relapse; this lead to establishment of FCR regimen as new gold standard in younger and physically fit patients. However, elderly and/or comorbid patients may not tolerate such aggressive approach due to high risk of unacceptable toxicity. To date, no randomized trials in this patient population have improved therapeutic results over chlorambucil; therefore, this agent remains the backbone of treatment against which the new protocols should be tested. Indeed, several currently running large trials investigate whether addition of an anti-CD20 monoclonal antibody (rituximab, obinutuzumab, ofatumumab) to chlorambucil yields better results. Performance status, biological age and number/severity of comorbid conditions should be incorporated into decision-making process with regard to intensity of treatment. Other emerging treatment alternatives for this patient population include fludarabine-based regimens in attenuated doses as well as protocols containing bendamustine or lenalidomide. Highdose steroids combined with rituximab might be a promising in relapsed/refractory CLL but infectious toxicity is serious. Finally, ofatumumab has been recently approved for the treatment of fludarabine and alemtuzumab-refractory patients. This article provides an overview of the current and future possibilities in the treatment of elderly and comorbid patients with CLL.

Treatment of recurrent or unresectable cutaneous and subcutaneaous tumors continues to be a major therapeutic challenge. Electrochemotherapy (ECT) is a palliative treatment of cutaneous and subcutaneous tumor nodules for which standard treatments (e.g. radiotherapy, chemotherapy, and surgery) have failed or proved to be insufficient. ECT combines the electropulsation of tumor cells (by local application of electric pulses) and the administration of antineoplastic drugs such as cisplatin or bleomycin (either intravenous or intratumoral). The permeability of the cancer cells to these poorly permeant anti-tumor drugs is transiently increased up to a hundred-fold. ECT is thus an efficient loco-regional therapy for palliative treatment of unresectable recurrent tumor nodules with overall objective response rates of approximatively 80-90% and has satisfactory cosmetic results. The next challenge for ECT is the treatment of deep-seated tumors and metastases. The joint therapy of ECT and electrotransfer of immune-stimulating genes or electro-photodynamic therapy could be a promising strategy for cancer eradication.

Cancer remains one of the leading causes of death in the Western world. Despite bold advances in therapeutic oncology, new drug development is infamously ineffective due to the lack of predictive in vitro models. Most patients that suffer from cancer do not die from the primary tumor but due to the development of metastases. And yet current in vitro screening methods for new drugs in oncology still largely target cytotoxicity or the inhibition of cell growth, in which a potential anti-metastatic activity cannot be assessed. Herein the current in vitro models in oncology are reviewed and a new rationale for the pre-clinical development of specific, anti-metastatic therapeutic agents is introduced.

The estrogen-related receptors (ERRs), comprising ERRα, ERRβ and ERRγ, are the members of the nuclear receptor superfamily, which have been functionally implicated in estrogen signal pathway in various patterns. However, no natural ligand of ERRs has been identified to data, so identification of the synthetic modulators (inverse agonist and agonist) of ERRs would be highly effective in the treatment of estrogen-related pathologies, such as diabetes, breast cancer and osteoporosis. This review summarizes the structures and biological functions of ERR subtypes, and the progress in designing the small molecular modulators of ERRs as well as the detailed description of available co-crystal structures of the LBD of ERRs in three distinct states: unligand, inverse agonist bound, and agonist bound.

Polymersomes are self-assembled spherical vesicles based on amphiphilic block copolymers. This review presents a summary of the achievements in the field of polymersome researches to date. Polymersomes have been applied as versatile drug carriers. Some polymersomes, which have well-known stimuli-responsibility, can release drugs in a controlled manner at the target site when they are given a specific stimulation such as pH, temperature, light, magnetic field, hydrogen bond actions, electrostatic force or ultrasound. The preparation methods of polymersomes are similar to that of liposomes, including the thin film rehydration technique, solvent method, direct dissolution, double emulsion in microfluidic device, and electroformation. In addition, biologically active ligands, such as antibodies, can be readily conjugated onto the exterior brush surface of polymersomes to target the vesicles or to provide a therapeutic response. Polymersomes offer superior advantages for future clinical therapeutic and diagnostic imaging applications.

Polymeric micelles (PMs) belong to supramolecular core-shell-type assemblies. PMs are from amphiphilic block copolymers with several tens of nanometers in diameter. An important criterion verifying the effectiveness of micellar drug carriers is the ability to control the location and time over which drug release occurs. The pH variations in the body are particularly important in the development of micellar carriers for treating diseases such as cancer and inflammation. pH-sensitive PMs have emerged as a fascinating class of nanoscopic drug carriers that can be elegantly applied for programmed drug and gene delivery. In this review, we provide an analysis of recent literature reports on these pH-sensitive PMs. Different approaches that have been taken to develop pH-sensitive PMs are highlighted, including incorporating pH-sensitive building blocks such as poly(L-histidine) and poly(β-amino ester), and acid degradable linkages such as hydrazones and acetals. The potential applications of pH-sensitive PMs within the biomedical field are also summarized.