Current Drug Targets - Volume 17, Issue 11, 2016

Rhabdomyosarcoma (RMS) is the most frequent pediatric soft-tissue tumor accounting for about 7% of childhood malignancies. Multimodal therapy is the standard treatment for individuals with RMS but generally fails to cure high-risk group patients and can result in long-term side effects. Therefore, understanding the mechanisms driving RMS might help to find new candidate targets for more specific and effective therapeutic modalities. One of the molecular machineries which is often deregulated in cancer and specifically involved in tumorigenesis of RMS, is Hedgehog (Hh) signaling. There is increasing evidence that targeting this developmental pathway may hold promise in future treatment strategies for RMS. In this review, we discuss the contribution of the Hh pathway in RMS, the challenges of inhibiting this embryonic signaling in children with an update on recent preclinical data and ongoing clinical trials.

The Notch signaling pathway is an evolutionarily conserved developmental network critical for embryonic and postnatal regulation of tissue growth, homeostasis, and repair. Signaling is initiated when transmembrane Notch ligands bind to transmembrane Notch receptors on nearby cells. Sequential proteolytic steps generate an activated Notch fragment that translocates to the nucleus, where it drives activation of canonical Notch target genes. In skeletal muscle, Notch signaling governs myogenic cell fate and stem cell maintenance. In the human soft tissue sarcoma rhabdomyosarcoma, which bears markers of skeletal muscle commitment and so is thought to be related to the skeletal muscle lineage, Notch signaling is also found to be upregulated and dysregulated. This review provides an overview of Notch signaling during normal embryonic and postnatal myogenesis, information on the recently discovered aberrant Notch signaling occurring in muscular dystrophies, the upregulation and mechanism of Notch signaling in the embryonal variant of rhabdomyosarcoma and related soft tissue sarcomas, and Notch cross-talk with other metazoan developmental pathways including Hippo, Hedgehog, Wnt, and TGF-β. The review concludes with updates on current promising efforts to target and inhibit Notch signaling in human sarcomas including rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in the pediatric population and recapitulates many of the phenotypic and biological features of embryonic skeletal muscle. RMS is pathologically characterized by myogenic differentiation arrest. Dysregulation of pathways essential for myogenesis like contribute to the tumorigenesis of RMS. The Wnt signaling pathway is one of the major pathways required for normal myogenesis. Aberrant Wnt signaling has also been demonstrated in many types of cancer. The role of Wnt pathway in the pathogenesis of RMS is beginning to be appreciated. This review will go over current knowledge on biological roles of Wnt pathway in RMS and potential translational application in therapeutics.

Diabetic nephropathy is the major cause of end-stage renal disease in Western societies. To date, interruption of the Renin-Angiotensin System is the most effective intervention for diabetic nephropathy, however these agents only slow progression of the disease. Thus, there is a major unmet need for new therapeutic targets. Aberrant activation of the receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic nephropathy via binding to a variety of ligands and inciting reactive oxygen species (ROS) production, inflammation and fibrosis. In recent years there have been considerable efforts in the development of effective RAGE antagonists, however, direct RAGE targeting may be problematic. Glucagon like peptide-1 (GLP-1) is an incretin hormone released by the L-cells of the small intestine to mediate glucose-dependent insulin release from pancreatic islets. The incretin-based therapies, GLP-1 receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors, are novel glucose-lowering agents used in type 2 diabetes. However, the extra pancreatic functions of GLP-1 have gained attention, including putative anti-apoptotic and anti-inflammatory properties. In rodent models of diabetes, incretin-based therapies are renoprotective. Interestingly, GLP-1 has been shown to interfere with the signalling and expression of RAGE. The current review aims to give an overview of the interactions between the RAGE and incretin pathways and to discuss the utility of targeting the GLP-1/incretin pathway in DN. It is possible that indirect targeting of RAGE through GLP-1 agonism will be of clinical benefit to patients with diabetic nephropathy.

Neuropeptides, and specifically Substance P (SP), can crucially contribute to the ocular inflammatory response. SP is an undecapeptide that is secreted from sensory nerve endings and from various immune cells during inflammation. SP modulates ocular inflammation through its binding with the high-affinity neurokinin-1 receptor (NK-1R). This receptor is expressed on nerves, immune cells, and epithelial cells. SP is a key mediator of neurogenic inflammation as it induces increased microvascular permeability, vasodilatation, plasma extravasation, and subsequent tissue edema. In addition, macrophages can release inflammatory mediators such as interleukins, chemokines, and growth factors in response to SP stimulation. Inhibition of SP activity, either through blockade of the neuropeptide release or the use of SP receptor antagonists, ameliorates ocular inflammation, it restores immune privilege and improves a number of clinical endpoints associated with inflammation, such as corneal opacity, ocular perforation, and angiogenesis. This review of the literature will summarize the role of SP in the ocular inflammatory response (with an emphasis on the ocular surface). In addition, it will review the therapeutic effects of SP blockade to control ocular inflammation (i) in animal models and (ii) in highly prevalent human diseases.

In the late 1980s, a loss-of-function mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel was identified to be the primary cause of cystic fibrosis (CF); a fatal multiple-organ disorder that mostly affects Caucasians. To date, approximately 2000 genetic mutations have been identified in the CFTR gene (http://www.genet.sickkids.on.ca/cftr/app). The most common cause of morbidity and mortality in persons with CF is a progressive deterioration in lung function leading ultimately to respiratory collapse. The median life expectancy of CF patients currently is estimated to be 39 years in the US. The most prevalent CFTR mutation, F508del, accounts for 70% of CF cases and causes a processing defect in the protein leading to premature endoplasmic reticulum-associated degradation (ERAD) and reduced F508del-CFTR delivery to the cell surface. A CF corrector is defined as a chemical chaperone that increases cell-surface levels of F508del-CFTR. A series of CF correctors have been developed, and VX-809 (lumacaftor) has been cited as the most effective symptomatic CF corrector to date. VX-809 improves the function of the mutant protein by approximately 15% in in vitro culture systems. However, this effect did not completely translate clinically, with only a marginal improvement observed in lung function of the F508del-homozygous patients undergoing the therapy. New studies revealed that even after successful ER retrieval, rescued F508del-CFTR (rF508del-CFTR) once at the cell surface does not function properly, exhibiting poor stability and channel gating and structural abnormalities. This becomes further complicated by the existence of genes termed CFTR modifiers, which can alter CFTR function to be additionally defective and exacerbate the CF phenotype while also alternatively suggested be potentially targeted to improve F508del-CFTR functional outcome. It is necessary to understand the biology of F508del-CFTR post-ER and at the plasma membrane where the protein might also confront the modifiers and how we can incorporate these components into CF therapeutics. Additionally, the notion that CF individuals would eventually benefit from more of a personalized medicine is becoming increasingly accepted. Here, we review how CF therapeutics may be simplified by understanding the complexities of rescued F508del-CFTR biology and eventually move toward more personalized medicine for patients suffering with CF.

The increasing prevalence of both obesity and depression is becoming a significant health concern throughout the world. Evidence suggests a positive and bidirectional association between obesity and depression. It is now well established that central serotonergic system is involved in the elicitation of satiety signal and elevation of mood. Drugs that increase serotonin neurotransmission are commonly recommended for the treatment of depression. But many patients are not benefitted by these drugs, while remission rate is also not satisfactory. Serotonin based antiobesity drugs have been either withdrawn from the market or disapproved for long term use. In view of critical need for novel therapeutic targets for obesity and depression, the role of leptin is becoming increasingly important. The peptide hormone secreted by adipocytes can cross blood brain barriers to elicit satiety signal via its receptors in the hypothalamus. Emerging evidence suggests that the peptide hormone has a role in responses to stress and produces antidepressant like effects. On the other hand, both obesity and depression are often associated with higher levels of leptin in circulation suggesting insensitivity to leptin. The aim of the present article is to draw research interest towards exploring mechanism involved in leptin resistance. These studies may facilitate the development of alternative treatment strategies, beyond serotonin based drugs, for obesity depression and their comorbid condition.

Apart from functioning as an energy source and important structural components of biological membranes, Free Fatty acids (FFAs) play a key role in the regulation of metabolic homeostasis. FFAs activate specific G-protein coupled receptors (GPCRs) in pancreatic β-cells, immune cells adipose, and intestine. GPR40 (also known as FFA receptor 1) is primarily expressed in pancreatic β-cells and is activated by medium-chain and long-chain FFAs. GPR40 has been shown to augment glucose dependent insulin secretion (GDIS) from pancreatic β-cells and is widely studied drug discovery target for the treatment of type 2 diabetes mellitus (T2DM) and other metabolic diseases. Several synthetic agonists of GPR40 augment insulin secretion from pancreatic β- cells and consequently improve glucose tolerance and restore metabolic homeostasis in various rodent models of T2DM. GPR40 agonists TAK-875 and AMG 837 have reached clinical trials and TAK 875 was shown to improve glycemic control in Type 2 diabetic patients. However, phase III clinical trials involving TAK-875 were recently terminated due to signs of liver toxicity in patients. Despite this setback, therapies based on GPR40 agonism provide an attractive alternative in the discovery of new anti-diabetic drugs. This review summarizes our current understanding of the physiological functions of GPR40, benefits and future prospects of GPR40 agonists to treat patients with T2DM.

The availability of new drugs capable of improving the overall survival of patients with metastatic castration-resistant prostate cancer has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit. The new agents have already been administered as third-line treatments in patients who have previously received them as second line in everyday clinical practice, but the efficacy of this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance has reinforced the debate concerning the best sequence to use in order to maximise the benefit. Furthermore, the situation is further complicated by the possibility of administering new hormonal agents to chemotherapy-naïve patients, and novel chemotherapeutic agents to hormone-sensitive patients. This article critically reviews the available data concerning the sequential use of new drugs, and discusses the real evidence concerning their optimal positioning in the therapeutic strategy of metastatic castration-resistant prostate cancer.

Diabetes is a metabolic disorder and over the past decades, it has become a major cause of morbidity and mortality affecting the youth and middle-aged as it is the fourth leading cause of disease related to death. In both type 1 and type 2 diabetes the severe pathogenesis cause micro vascular complications: nephropathy, retinopathy, neuropathy and macro vascular complications: cardiovascular disease, heart attacks and stroke. Under hyperglycemia, activation of different signaling mechanisms such as an increased polyol pathway, advanced-glycation end product formation, activation of Protein Kinase C and hexosamine pathway leads to the over expression of reactive oxygen species and causes pathogenesis of diabetic complications. It is necessary to understand these pathways in diabetic complications causing damage to the secondary system of the body. In the past decade the understanding of these biochemical changes has increased tremendously and various molecules have been exploited as therapeutic targets for diabetic complications as better therapeutic approach. In this review, a brief overview about diabetes mellitus and chronic complications with their current understandings of cellular/molecular mechanisms and targeted therapies along with novel therapeutic strategies is discussed.