Editorial [Hot Topic: Towards Tailored Treatment - New Organ-Specific Drug Strategies Interfering in Signal Transduction (Guest Editors: Jai Prakash and Martin H. de Borst)]

Cells regulate normal physiological function by receiving signals from outside as well as providing signals to other cells. These signals are mediated through cytokines, hormones or growth factors which bind to their cognate receptors and trigger receptor-mediated signaling cascades. G-protein coupled receptor kinase, receptor tyrosine kinase, integrin and toll-like receptor pathways cover the most receptor-mediated signaling pathways. Apart from cell surface receptors-generated signaling pathways, intracellular receptor-mediated pathways also exist for which ligands such as thyroid hormones, steroid hormones etc need to cross the membrane and bind to its intracellular receptor. Under pathophysiological conditions, these signaling pathways are deregulated, resulting in intra- as well as intercellular miscommunication due to production of unwanted signals, leading to progression of the disease. Interruption of these signaling pathways using small molecules has emerged as a pivotal approach to treat a number of diseases. Unlike conventional approaches of blocking or activating a receptor, signaling inhibitors interfere in the intracellular signaling cascades either at upstream or downstream level. Blocking of an upstream signaling pathway may block a wide range of signals elicited by a receptor ligand. Inhibition of a downstream pathway provides relatively higher specificity to a therapy as only a specific transcriptional process will be affected. Most of the signaling inhibitors were developed for cancer treatment and named as “targeted therapies”. These therapies include small inhibitors of protein kinases that modify other proteins by adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change of the target protein by changing its activity, cellular location, or association with other proteins. Some protein kinases are mutated to be constitutively active in tumor cells and inhibitors of such kinases would be specific for cancer cells. Imatinib mesylate (Glivec®), an inhibitor of BCR-ABL (a cancer-related tyrosine kinase) and PDGF-R tyrosine kinases, was the first one to get approval by FDA in 2001 for the treatment of gastrointestinal stromal tumor and several types of leukemia. Its success started a new era in cancer therapy and since then many TKIs have made their way to the clinic including Gefitinib (Iressa®) and Lapatinib (Tykerb®) against EGF receptor, Sorafenib (Nexavar®) and Sunitinib (Sutent®) against many kinases including PDGF and VEGF receptors. Other dozens of kinase inhibitors are now in clinical trials. Apart from cancer, many other diseases are now potential targets for treatment using signaling inhibitors. However, signaling pathways are generally involved in the regulation of normal physiological functions and inhibition of these pathways ubiquitously would result in side effects in other organs. To make these therapies more specific to the affected organ, many new approaches have been applied. In this special issue, we aimed to provide instances of strategies used for organ-specific signaling inhibition. This issue encompasses review articles focused on the strategies used to target brain disorders, chronic kidney disease, liver disease (hepatocellular carcinoma), cancer, and inflammatory/autoimmune disorders. Wisler and co-authors review thoroughly the organ-specific therapies for autoimmune diseases such as Sjogren's syndrome, inflammatory bowel diseases or Crohn's disease and rheumatoid arthritis in their article [1]. These disorders are mainly characterized by deregulated innate and defective acquired cellular and humoral immune responses. As a result many proinflammatory cytokines (TNF-α, many interleukins and interferons) are induced systemically and in the affected organ where these cytokines activate many intracellular signaling pathways such as SAPK/MAPK, JAK/STAT and PI3K/PTEN/Akt/mTOR pathways. The authors have clearly described the disease mechanisms in detail including role of different cytokines and their signaling pathways in three disorders. To support the information, they have also reviewed the in vivo data. For Sjogren's syndrome, anti-TNF-α strategies mostly based on capturing TNF-α using monoclonal antibodies or soluble receptor have been covered. Similarly, monoclonal antibodies and small signaling inhibitors used experimentally or clinically have been discussed for inflammatory bowel disease and rheumatoid arthritis. Most interestingly, authors report literature on organ-specific drug delivery approaches to make these inhibitors selective to target organs. These approaches include drug targeting using immunoliposomes, humanized antibodies, aptamers, organ-specific peptides and the use of lectins and lectin-binding saccharides. Of interest, targeting of anti-inflammatory cytokines such as IL-10 to inflamed vasculature by coupling compounds to a fusion protein has also been addressed in this review. Together, this review provides a comprehensive overview of the interplay of various signaling pathways and newest targeted approaches to treat inflammatory/autoimmune diseases. As discussed above, signalling inhibitors have primarily been applied for cancer therapeutics but yet require more specificity to cancer tissue. Altintas and co-authors have elaborated this topic in their review reported in this issue [2]. They clearly explain why tumor-specific targeting of the so-called targeted therapies is essential. Some tyrosine kinases are selectively present in tumor cells but most of the others are also actively present in normal tissues. Inhibitors of EGF and VEGF receptor kinases, especially for cancer therapies, have been reported to display serious side effects such as cardiotoxicity in long-term use. Furthermore, the authors describe in detail several drug delivery tools such as liposomes, polymers, microspheres, and drug-protein conjugates. Targeting to tumors can be through Enhanced Permeability and Retention (EPR)- mediated effects which is mostly applicable to particulate system such as liposomes, nanoparticles, etc. In contrast, use of peptides, monoclonal antibodies and proteins to deliver signalling inhibitors into cells are active receptor-mediated endocytosis process. In addition, new linking technology to conjugate these inhibitors to different carriers has also been incorporated in this article. In addition, this review covers up the latest examples of targeted signalling inhibitors (chemical structures) examined in vivo. In continuation of the topic of tumor targeting, Farinati et al. have contributed a review on (targeting of) signalling inhibitors to hepatocellular carcinoma [3]. As the authors indicate, the diagnostics and therapy of early stages of hepatocellular carcinoma have tremendously improved, although for intermediate and advanced stages the therapeutic options are far from optimal. The authors will discuss in detail the role of growth factors and their receptors. Particular attention is given to vascular endothelial growth factor (VEGF), as this factor has been identified as a major factor involved in angiogenesis. Additionally, epidermal growth factor (receptor), insulin-like growth factor (receptor) and platelet-derived growth factor are discussed as targets for intervention in hepatocellular carcinoma. More downstream of these growth factor receptors, intracellular pathways play a role in hepatic carcinogenesis. Pathways that have been targeted include mitogen-activated protein kinases and PI3KAkt/ mTOR. In their review paper, Farinati et al. put an emphasis on recent developments from clinical trials in hepatocellular carcinoma, which are excellently summarized.....