Current Drug Targets (v.17, #6)

Meet Our Editorial Board Member by Tetsumei Urano (617-617).

CD6 has been exploited as a drug target as its expression is restricted, primarily to T cells, it has a well characterised cell surface ligand, CD166 and regulates T cell activation through a long cytoplasmic tail. CD6 can affect both the initiation and maintenance of T cell function in a negative and positive manner respectively so that it is important to understand these dual effects of a potential drug target. The effective mode of action of clinical monoclonal antibodies (mAbs) that recognise cell surface receptors including CD6 is commonly cytotoxic depletion of cells. It is not clear how current therapeutic strategies to target CD6 perturb function. With the benefit of new structural data, this review provides a critical analysis and interpretation of experiments in which various reagents have been tested and offers some suggestions as how more effective drugs may be developed.

Tuning T Cell Activation: The Function of CD6 At the Immunological Synapse and in T Cell Responses by Rita F. Santos, Liliana Oliveira, Alexandre M. Carmo (630-639).
CD6 immunotherapy to treat psoriasis and rheumatoid arthritis has reached the clinical trial stage with apparent success, and targeting CD6 with mAbs is being used in several animal models of autoimmunity and neuroinflammation with promising indications. However, the mode of action of the therapeutic CD6 mAbs is far from being understood, reflecting the uncertainties and controversy surrounding the mechanistic and biological functions of CD6. Initially regarded as a co-stimulatory receptor of T lymphocytes, recent studies suggest that CD6 can instead modulate early as well as late T cell responses. Also, opposing the contribution of CD6 adhesiveness in the establishment and stabilization of immunological synapses, the actual triggering of CD6 might induce anti-proliferative signals to the T lymphocyte. CD6 has an unusually long cytoplasmic tail and its gene undergoes peculiar patterns of activation-dependent alternative splicing that can on one hand determine whether or not the CD6 protein binds to its ligand, and on the other include or exclude intracellular sequences that may transduce positive or negative signaling. In this review we discuss the multiple aspects that determine the nature of the signals transmitted via CD6 and the context that may define a dual role for this important T cell surface molecule.

Pattern Recognition by CD6: A Scavenger-Like Lymphocyte Receptor by Adelaida Sarukhan, Mario Martinez-Florensa, Cristina Escoda-Ferran, Esther Carrasco, Esther Carreras, Francisco Lozano (640-650).
CD6, one of the first antigens to be identified on T cells, is a membrane glycoprotein that physically associates with the antigen receptor complex. Because of this, its main function seems to involve the modulation of TCR-mediated signaling pathways. However, growing evidence indicates that this ancient and conserved scavenger-like receptor may also play a role as pattern recognition receptor (PRR), similar to other members of the scavenger receptor cysteine rich superfamily (SRCR-SF). Here, we discuss the functional interactions of CD6 with microbe- and damage-associated signals and the potential use of soluble forms of CD6 in the therapeutic treatment of bacterial infections, in particular multi-drug resistant bacterial strains. Importantly, microbe recognition by CD6 may also have functional consequences on T cell activation and differentiation, which remain to be explored.

The Link Between CD6 and Autoimmunity: Genetic and Cellular Associations by David M. Kofler, Aron Farkas, Michael von Bergwelt-Baildon, David A. Hafler (651-665).
The cell surface glycoprotein CD6 is expressed on leukocytes and mediates T cell trafficking across endothelial cell barriers. There is evidence suggesting that CD6 is implicated in the pathogenesis of autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). CD166, the physiological ligand of CD6, is expressed on endothelial cells in the central nervous system and in the collagen tissue of joints as well as on the cell surface of synovial fibroblasts. Animal models and in vitro experiments have shown that CD166 facilitates leukocyte trafficking into the central nervous system and mediates interactions of synovial cells with T lymphocytes, thereby representing a possible common mechanism of pathogenesis in MS and RA. In recent years, genome-wide association studies (GWAS) have established a genetic link between CD6 and MS. The single nucleotide polymorphism (SNP) rs17824933 in the CD6 gene has been identified and validated as a genetic risk factor for the development of MS. The SNP is associated with altered CD4+ T cell functions and with the expression of alternative CD6 splice variants in T cells. Several other independent CD6 gene polymorphisms have been associated with disease susceptibility or with clinical features such as worse attack recovery in MS. In addition to the genetic associations found in MS, an allelic variant of the CD6 gene correlates with clinical response to tumor necrosis factor- (TNF-) inhibitors in patients with RA. Preliminary data indicate that anti-CD6 blockade may be a promising tool for the treatment of RA and psoriasis. Taken together, genetic associations and clinical observations provide new evidence for a role of CD6 in autoimmunity.

Therapeutic Targeting of CD6 in Autoimmune Diseases: A Review of Cuban Clinical Studies with the Antibodies IOR-T1 and Itolizumab by Patricia Hernández, Ernesto Moreno, Lazaro E. Aira, Pedro C. Rodríguez (666-677).
The CD6 molecule is a pan T cell marker involved in T cell regulation. Although CD6 expression has been correlated with human autoimmune diseases, only a few therapeutic approaches are exploring this molecule as target in the clinic. The biological functions and mechanisms of actions of CD6 have not been definitively established. It is probable that this molecule plays a dual role as a modulator of intracellular signaling. Itolizumab is a humanized monoclonal antibody specific for human CD6, developed at the Center of Molecular Immunology in Havana, Cuba. Its parent murine antibody, the IOR-T1 mAb, had been obtained in the 80's at the Institute of Oncology and Radiology, also in Havana. This article provides an overview of the clinical data obtained in Cuban patients with autoimmune diseases who have been treated with IOR-T1 mAb or itolizumab. Furthermore, we discuss the possible mechanism of action of itolizumab basing the analysis on recent site mutagenesis and structural data, which, contrary to previous interpretations, points to a steric blocking of the CD6-CD166 interaction in the cellular context. Overall, the conducted clinical studies have demonstrated that itolizumab has favorable clinical effects and a safety profile when used as monotherapy in patients with rheumatoid arthritis and psoriasis. So far, in vitro and in vivo evidences indicate that itolizumab has immunomodulatory and anti-inflammatory effects. Hence, itolizumab represents a new therapeutic option for autoimmune diseases such as rheumatoid arthritis and psoriasis.

Cancellers - Exploring the Possibility of Receptor Decoy Traps As a Superior Anti-Retroviral Strategy by Sundararaj Stanley Jeremiah, Kenji Ohba, Naoki Yamamoto (678-692).
The global Human Immunodeficiency Virus (HIV) pandemic is still spreading due to the lack of ideal anti-retroviral measures and their availability. Till date, all attempts to produce an efficient vaccine have ended with unsatisfactory results. The highly active anti-retroviral therapy (HAART) is the only effective weapon currently available and is widely being used for curtailing the HIV pandemic. However, the HAART is also expected to fail in the near future due to the emergence and dissemination of antiviral resistance. This review sheds light on the reasons for the failure of the conventional anti-viral measures against HIV and the novel anti-retroviral strategies currently being developed. The various principles to be considered for the success of a novel anti-retroviral strategy are elaborately emphasized and an innovative concept is proposed on these lines. The proposed concept intends to use receptor decoy traps (RDT) called cancellers which are erythrocytes expressing the HIV entry receptors on their surface. If successfully developed, the cancellers would be capable of active targeting of the free HIV particles leading to the trapping of the viruses within the canceller, resulting in the neutralization of infectivity of the trapped virus. The possible ways of translating this concept into reality and the probable hurdles that can be encountered in the process are subsequently discussed. Also, the scope of cancellers in therapeutic and/or preventive strategies against HIV infection is envisaged upon their successful development.

Dormant Circulating Tumor Cells in Prostate Cancer: Therapeutic, Clinical and Biological Implications by Maria J. Alvarez-Cubero, Fernando Vázquez-Alonso, Ignacio Puche-Sanz, F. Gabriel Ortega, M. Martin-Prieto, José L. Garcia-Puche, Manrique Pascual-Geler, José A. Lorente, José M. Cozar-Olmo, Maria J. Serrano (693-701).
Circulating Tumor Cells (CTCs) are a valuable prognostic factor in several solid tumors. By understanding the biological characteristics of CTCs we could better understand the biology of metastasis. CTCs usually adopt a dormant state that is believed to be a strategy to survive in extreme conditions. To enter a dormant state, CTCs undergo numerous phenotypic, genetic and functional mutations that significantly affect the efficacy of the therapies used to kill dormant CTCs. Hence, understanding the biological events involved in the dormancy process of CTCs would allow the identification of new therapeutic targets. Some experimental studies or preclinical models have explored these biological events, as well as the molecular factors that contribute to the maintenance of and release from dormancy. However, few studies have assessed the effects of anticancer therapies on dormant cells. This study reviews current the data currently available on cell dormancy mechanisms in prostate cancer, with a special focus on the functional, genetic and phenotypic plasticity of CTCs and their potential implications in the clinical and therapeutic management of prostate cancer.

The increasing multi-drug resistance has become a major threat to the public health. Overexpression of multidrug efflux pumps is one of the major mechanisms of drug resistance in bacteria. Since active efflux of antibacterial agents plays a significant role in mediating drug resistance in bacteria, the inhibition of efflux pumps appears to be a promising strategy to restore antibacterial potency. In recent years, in order to address this grave problem of multiple drug resistance mediated by efflux pump, a large number of efflux pump inhibitors have been discovered and tested, including natural products, antibiotics and synthetic molecules. This review mainly describes recent achievements in the search for new molecules that are able to inhibit efflux pumps in both Gram-positive and Gram-negative bacteria, in particular emphasis on natural and synthetic inhibitors of the NorA efflux pump in Staphylococcus aureus, MexAB-OprM efflux pump in Pseudomonas aeruginosa, and AcrAB-TolC efflux pump in Enterobacteriaceae, giving special attention to their mechanisms of action, structureactivity relationships and synergetic effect with clinically available antibiotics.

Advances in Hyaluronic Acid-Based Drug Delivery Systems by Yan Jiao, Xin Pang, Guangxi Zhai (720-730).
Hyaluronic acid (HA) is a relatively new polymer for the construction of drug delivery systems. CD44 and the receptor for HA-mediated motility play a key role in vivo for the receptormediated endocytosis of HA. Cellular uptake and the efficiency of tumor-targeted drug delivery are supposed to increase through utilizing HA as drug carriers. Currently, HA has provided a promising platform to physically encapsulate or chemically conjugate with various drugs. In this review, we presented the most latest advances in HA-based drug delivery systems and some forward-looking ideas are discussed.

New Antimicrobial Approaches: Reuse of Old Drugs by Dianella Savoia (731-738).
The global situation of antibiotic resistance and the reduction of investments in antibiotics research by the pharmaceutical industry suggest the need for specific cost-effective approaches in order to identify drugs for the therapy of many microbial infections. Among the viable alternative antiinfective compounds, drug repurposing, i.e. to find new uses for previously approved medicines, revealed some encouraging in vitro and in vivo results. In this article the reader has a panoramic view of the updated references on the strategies encountered during the repositioning process. New findings are reported about the anti-microbial efficacy of antipsychotic, cardiovascular, anti-inflammatory and anti-neoplastic drugs. This approach may enhance the portfolio of pharmaceutical companies reducing the need for pharmacokinetic and toxicity studies; the development of new uses of old drugs for different infectious diseases, leading to better health for patients, also in poor, tropical countries, appears to be having better results.

Anaplastic Lymphoma Kinase Inhibitors in Non-Small Cell Lung Cancer by David M. Straughan, Sad C. Azoury, Vivek Shukla (739-745).
Lung cancer is the leading cause of cancer death among both sexes in the United States and non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Over the last several decades, there have been many advances in both surgical approaches and systemic therapies for the treatment of NSCLC, but the prognosis for advanced disease remains poor. New research, however, is exploring the use of targeted therapies for the treatment of NSCLC. The anaplastic lymphoma kinase (ALK) is involved in normal mammalian central nervous system development. A novel fusion gene involving ALK and the echinoderm microtubule-associated protein-like 4 (EML4) gene has been associated with approximately 5% of NSCLCs and is mutually exclusive of other oncogenic driver mutations. Targeted therapies against this ALK rearrangement are a relatively new treatment modality that aims to improve the prognosis of patients with late-stage disease. Two such drugs have Food and Drug Administration (FDA) approval currently: Crizotinib and Ceritinib. Many other ALK inhibitors are currently being studied in clinical trials as well. The authors aim to provide a comprehensive review of ALK inhibitors for use in NSCLC as well as the future directions and challenges to developing these targeted therapies.