Telomerase as a therapeutic target. Therapeutic potential of telomerase inhibitors.
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Antineoplastic Agents↗
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Epigenetic transitions: towards therapeutic targets.
Therapeutic approaches aimed at developing epigenetically-effective drugs are under intense investigation. Several classes of enzymes regulating histone acetylation and DNA methylation, which are required for epigenetic transitions, offer attractive targets for therapeutic interventions. Imbalances in histone acetylation and DNA methylation may play a significant role in the development of cancer and leukaemia and may provide a mechanistic rationale for targeting epigenetic modifications. Clinical trials designed to evaluate inhibitors of DNA methylation and histone deacetylase inhibitors are showing encouraging results in cancer patients. A growing quantity of data from preclinical research supports the notion that epigenetically-effective drugs could also find an application in other therapeutic areas. A number of emerging biomarkers may prove useful for monitoring drug effects and defining molecular signatures of response, toxicity and effective dose.
Acetylation↗
Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?
For many years, heat shock or stress proteins have been regarded as intracellular molecules that have a range of housekeeping and cytoprotective functions, only being released into the extracellular environment in pathological situations such as necrotic cell death. However, evidence is now accumulating to indicate that, under certain circumstances, these proteins can be released from cells in the absence of cellular necrosis, and that extracellular heat shock proteins have a range of immunoregulatory activities. The capacity of heat shock proteins to induce pro-inflammatory responses, together with the phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins, has led to the proposition that these proteins provide a link between infection and autoimmune disease. Indeed, both elevated levels of antibodies to heat shock proteins and an enhanced immune reactivity to heat shock proteins have been noted in a variety of pathogenic disease states. However, further evaluation of heat shock protein reactivity in autoimmune disease and after transplantation has shown that, rather than promoting disease, reactivity to self-heat shock proteins can downregulate the disease process. It might be that self-reactivity to heat shock proteins is a physiological response that regulates the development and progression of pro-inflammatory immunity to these ubiquitously expressed molecules. The evolving evidence that heat shock proteins are present in the extracellular environment, that reactivity to heat shock proteins does not necessarily reflect adverse, pro-inflammatory responses and that the promotion of reactivity to self-heat shock proteins can downregulate pathogenic processes all suggest a potential role for heat shock proteins as therapeutic agents, rather than as therapeutic targets.
Journal Article↗
The emerging market dynamics of targeted therapeutics.
Targeted biotech drugs that attack specific biological molecules that cause disease are bringing new benefits even as they foment pricing dynamics that are very different from those of traditional drugs. Targeted drugs tend not to compete with each other even when treating closely related diseases, which makes them resistant to price controls. We can expect the supply of expensive new so-called biotech drugs to continue. But the same properties that generate premium prices also facilitate inventing around successful drugs, eventually leading to vigorous competition despite the lack of generic alternatives.
Biotechnology↗
Microbes: therapeutic targets or therapeutic tools?
Antimicrobial resistance has produced alarming situation worldwide. Use of antibiotics in large scale is one of the common cause for developing microbial resistance. Newer and newer antibiotics are coming for their use and more resistance problem is arising out. A complete new method of treatment by bacterial interference has been evolved. However, a new method of treatment has evolved ie, bacterial interference.
Anti-Bacterial Agents↗
Neuroinflammation: a potential therapeutic target.
The increased appreciation of the importance of glial cell-propagated inflammation (termed 'neuroinflammation') in the progression of pathophysiology for diverse neurodegenerative diseases, has heightened interest in the rapid discovery of neuroinflammation-targeted therapeutics. Efforts include searches among existing drugs approved for other uses, as well as development of novel synthetic compounds that selectively downregulate neuroinflammatory responses. The use of existing drugs to target neuroinflammation has largely met with failure due to lack of efficacy or untoward side effects. However, the de novo development of new classes of therapeutics based on targeting selective aspects of glia activation pathways and glia-mediated pathophysiologies, versus targeting pathways of quantitative importance in non-CNS inflammatory responses, is yielding promising results in preclinical animal models. The authors briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to onset or progression of neurodegenerative diseases. The authors conclude with opinions based on recent experimental proofs of concept using preclinical animal models of pathophysiology. The focus is on Alzheimer's disease, but the concepts are transferrable to other neurodegenerative disorders with an inflammatory component.
Animals↗
Molecular optical imaging of therapeutic targets of cancer.
Recent progress in discerning the molecular events that accompany carcinogenesis has led to development of new cancer therapies directly targeted against the molecular changes of neoplasia. Molecular-targeted therapeutics have shown significant improvements in response rates and decreased toxicity as compared to conventional cytotoxic therapies which lack specificity for tumor cells. In order to fully explore the potential of molecular-targeted therapy, a new set of tools is required to dynamically and quantitatively image and monitor the heterogeneous molecular profiles of tumors in vivo. Currently, molecular markers can only be visualized in vitro using complex immunohistochemical staining protocols. In this chapter, we discuss emerging optical tools to image in vivo a molecular profile of risk-based hallmarks of cancer for selecting and monitoring therapy. We present the combination of optically active, targeted nanoparticles for molecular imaging with advances in minimally invasive optical imaging systems, which can be used to dynamically image both a molecular and phenotypic profile of risk and to monitor changes in this profile during therapy.
Animals↗
The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation.
Autoimmune inflammatory responses and the diseases that develop as a consequence are now thought to be driven through a novel non-Th(1) pathway. IL-23, together with additional factors including TGF-beta1 and IL-6, collectively generate and sustain a distinct CD4(+) 'Th(17) inflammation effector' T-cell subset characterized by its production of inflammatory chemokines and cytokines, including IL-17. With this paradigm shift in understanding of autoimmune inflammation pathogenesis comes exciting opportunities to identify and to target therapeutically molecules within the IL-23/Th(17) axis that are key to disease development.
Animals↗
Mechanisms of action for treatments in multiple sclerosis: Does a heterogeneous disease demand a multi-targeted therapeutic approach?
The etiology of multiple sclerosis (MS) is incompletely understood, and evidence suggests there may be more than one underlying cause in this disorder. Furthermore, this complex and heterogeneous autoimmune disease shows a high degree of clinical variability between patients. Therefore, in the absence of a single therapeutic target for MS, it is difficult to apply conventional drug design strategies in the search for new treatments. We review the potential mechanisms of action of several effective therapies for MS that are currently available or in development. The effects of each treatment are described in terms of their actions on key processes in a five-step model of MS pathogenesis. Conventional immunosuppressants targeting intracellular ligands (e.g. mitoxantrone) have broad cytotoxic effects on B cells, T cells, and macrophages. This suppresses the pathogenic immune response in MS with high efficacy but is also associated with high toxicity, limiting the long-term use of these agents. Monoclonal antibodies (e.g. natalizumab and alemtuzumab) are a new generation of immunosuppressants that act on immune-cell surface ligands. These agents have narrower immunosuppressive actions and different safety profiles compared with conventional immunosuppressants. Immunomodulators (interferon-beta and glatiramer acetate), which shift the immune balance toward an anti-inflammatory response, are at the frontline of treatments for MS. Immunomodulators have targeted actions on the immune system, but affect a greater number of immunopathogenic processes than monoclonal antibodies. Given the inherent heterogeneity of MS, such treatments, which act at many levels of the disease, may achieve the best clinical results. Using our understanding of the interplay between mechanism of action and clinical effects in MS therapies may help us to better design and select new treatments for the future.
Adjuvants, Immunologic↗
The EGF receptor family as therapeutic targets in breast cancer.
Many studies have suggested an association between overexpression of receptor tyrosine kinases (RTKs) from the EGF receptor (or ErbB) family and breast cancer. The orphan RTK ErbB2/HER2/Neu is highly overexpressed in up to 30% of human breast cancer cases as a consequence of gene amplification. ErbB2/HER2/Neu can be activated by simple overexpression, and its signaling is thought to play an important role in initiation and progression of ErbB2-positive breast cancers. In support of this, ErbB2/HER2/Neu-targeted therapy (the Herceptin antibody) has proven valuable in many of these cases. Other studies also correlate EGF receptor (EGFR) expression with poor prognosis in breast cancer, but follow-up studies suggest that this association is much less robust than with ErbB2, and requires more careful analysis. A particular problem is that EGFR, unlike ErbB2/HER2/Neu, cannot be activated simply by overexpression, its signaling remaining growth factor-dependent under these conditions. It is therefore critical to analyze EGFR signaling activity itself, rather than simply EGFR expression, in order to establish causal links and to identify patients for ErbB-targeted therapies. This distinction between ErbB2/HER2/Neu and EGFR is satisfyingly explained by recent crystallographic studies of ErbB receptor family members that are reviewed here. These structures also provide new insight into how ErbB2/HER2/Neu-targeted and EGFR-targeted therapeutic agents function, and suggest approaches for the development of novel mechanism-based ErbB inhibitors.
Journal Article↗
The cardiac gap junction: a potential therapeutic target in the treatment of heart disease.
Cardiac gap junctions have been implicated in maintaining cardiac conduction and function. In cardiac disease, expression of connexin 43, the most abundant ventricular gap junction protein, is markedly abnormal, a process termed gap junction remodeling. To date, however, the gap junction has not been directly targeted therapeutically in cardiac disease states. Therefore, we have developed novel and complementary experimental models to investigate whether loss of connexin 43 expression in the heart can be directly linked to the arrhythmic and functional complications of heart disease. In this article, we discuss how data from connexin 43 conditional and chimeric knock-out mice support the hypothesis that gap junction remodeling is a key molecular feature underlying the high incidence of sudden arrhythmic death and exacerbating the ventricular dysfunction associated with acquired heart disease.
Animals↗
AACR-NCI-EORTC--17th Symposium: Molecular Targets and Cancer Therapeutics. Targeting regulatory proteins.
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Animals↗
Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies.
Angiogenesis, the growth of a network of blood vessels, is a crucial component of solid tumour growth, linking the relatively harmless avascular growth phase and the potentially fatal vascular growth phase. As a process, angiogenesis is a well-orchestrated sequence of events involving endothelial cell migration, proliferation; degradation of tissue; new capillary vessel (sprout) formation; loop formation (anastomosis) and, crucially, blood flow through the network. Once there is blood flow associated with the nascent network, the subsequent growth of the network evolves both temporally and spatially in response to the combined effects of angiogenic factors, migratory cues via the extracellular matrix and perfusion-related haemodynamic forces in a manner that may be described as both adaptive and dynamic. In this paper we present a mathematical model which simultaneously couples vessel growth with blood flow through the vessels--dynamic adaptive tumour-induced angiogenesis (DATIA). This new mathematical model presents a theoretical and computational investigation of the process and highlights a number of important new targets for therapeutic intervention. In contrast to earlier flow models, where the effects of perfusion (blood flow) were essentially evaluated a posteriori, i.e. after generating a hollow network, blood flow in the model described in this paper has a direct impact during capillary growth, with radial adaptations and network remodelling occurring as immediate consequences of primary anastomoses. Capillary network architectures resulting from the dynamically adaptive model are found to differ radically from those obtained using earlier models. The DATIA model is used to examine the effects of changing various physical and biological model parameters on the developing vascular architecture and the delivery of chemotherapeutic drugs to the tumour. Subsequent simulations of chemotherapeutic treatments under different parameter regimes lead to the identification of a number of new therapeutic targets for tumour management.
Animals↗
Folate receptors as potential therapeutic targets in choroid plexus tumors of SV40 transgenic mice.
A high affinity folate receptor is expressed in some human cancers, including choroid plexus tumors and ependymomas, and has been suggested as a target for therapeutics. In this report, the expression of folate receptors in an SV40 large T antigen transgenic mouse (SV11) was investigated. SV11 mice develop choroid plexus tumors, a property that may be related to the observation that SV40 has been isolated from human choroid plexus tumors and ependymomas. We report that SV11 choroid plexus tumors contain a high affinity folate receptor (KD of 1 nM), detectable by 125I-folate autoradiography and immunohistochemistry. Western blot analysis indicated an apparent molecular weight of 38 kDa. RT-PCR revealed the presence of transcripts for both alpha and beta isoforms of the folate receptor. Brain parenchyma has undetectable folate receptor, but normal choroid plexus has substantial levels (as does human choroid plexus). The folate receptors of the tumor are accessible from the bloodstream whereas those of the normal choroid plexus are not. Thus SV11 transgenic mice should be useful for evaluating therapeutic targeting of high affinity folate receptors, both for efficacy of specific agents and possible side effects.
Animals↗
The ubiquitin-proteasome pathway as a therapeutic target for muscle wasting.
Atrophy of skeletal muscle is common to a number of conditions, including cancer, sepsis, AIDS, renal failure, diabetes, severe trauma, and burns. In all cases, protein synthesis in skeletal muscle is depressed, whereas protein degradation is increased through an increase in activity and expression of the ubiquitin-proteasome proteolytic pathway. This pathway is not responsive to simple nutritional intervention. Certain agents, including glucocorticoids, cytokines, proteolysis-inducing factor (PIF), and oxidative stress, are thought to be responsible for the induction of the ubiquitin-proteasome pathway in skeletal muscle in catabolic conditions. Insulin suppresses activation of this pathway, and loss of insulin action in diabetes leads to muscle wasting. Cytokines, PIF, and reactive oxygen species (ROS) are thought to induce proteasome expression through activation of the transcription factor nuclear factor kappa B (NF-kappaB). Targets for therapeutic intervention include antagonists of the inducers of proteasome expression, intracellular signaling pathways leading to activation of NF-kappaB, and the enzymes inducing ubiquitin conjugation to the substrate protein (myosin), as well as the proteasome itself. Anticytokine and anti-PIF antibodies are effective in attenuating muscle protein degradation in certain experimental animal models,and glucocorticoid receptor antagonists are effective in the treatment of sepsis. Agents that inhibit NF-kappaB activation, such as resveratrol, thalidomide, ibuprofen, eicosapentaenoic acid, and beta-hydroxy-beta-methylbutyrate, are effective in the preservation of skeletal muscle mass in cachexia. These results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to prevent muscle wasting.
Blood Proteins↗
Functional dyspepsia: drugs for new (and old) therapeutic targets.
The therapeutic management of functional dyspepsia remains a major challenge for the gastroenterologist. Current therapies available are based on putative underlying pathophysiologic mechanisms, including gastric acid sensitivity, slow gastric emptying and Helicobacter pylori infection, but only a small proportion of patients achieve symptomatic benefit from these therapeutic approaches. Relatively novel mechanistic concepts under testing include impaired gastric accomodation, visceral hypersensitivity, and central nervous system dysfunction. Serotonergic modulators (e.g. the 5-HT4 agonist tegaserod, the 5-HT3 antagonist alosetron and the 5-HT1P agonist sumatriptan), CCK-1 antagonists (e.g. dexloxiglumide), opioid agonists (e.g. asimadoline), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g dextromethorphan), neurokinin antagonists (e.g. talnetant), capsaicin-like agents and antidepressants are among the agents currently under investigation. It seems unlikely, however, that targeting a single mechanism with an individual drug will result in complete symptom remission in most cases.
Dyspepsia↗
Interleukin-6: a new therapeutic target.
The therapeutic success of biological agents, especially the tumour necrosis factor (TNF) inhibitors, has opened a new chapter in the book of therapies for rheumatoid arthritis. Nevertheless, more than 50% of patients may not respond by > 50% improvement. New compounds have recently entered the treatment arena. One of these is rituximab, which depletes B cells, and another, abatacept, interferes with T-cell co-stimulation. However, although these agents may be effective in a number of patients who fail to respond to TNF blockade, they only rarely induce remission and overall 50% response rates do not exceed those with the TNF inhibitors. Among the major proinflammatory cytokines, IL-6 plays a pleiotropic role both in terms of activating the inflammatory response and osteoclastogenesis. Here, we review recent phase II trials of tocilizumab, a humanized anti-IL-6 receptor antibody that achieves a significant therapeutic response rate.
Acute-Phase Reaction↗
G protein-coupled receptors and their signaling pathways: classical therapeutical targets susceptible to novel therapeutic concepts.
In recent years, new strategies in cancer therapy have been developed targeting key signaling molecules in the receptor tyrosine kinase signal transduction pathway. In contrast, most therapeutical concepts to manipulate G protein-coupled receptors (GPCR)-mediated disorders are still limited to the use of receptor-specific agonists or antagonists. Visible progress in the understanding of GPCR signaling complexity, especially the detection of several families of highly target- and cell-specific regulator proteins of GPCRs, G proteins, and effector components may open new horizons to develop novel therapeutical concepts targeting GPCR signaling elements. Thus, this review will focus on different molecular levels that may be of particular interest in terms of new drug development such as: (i) GPCR subtypes, allosteric binding sites, dimerization and constitutive activity, the use of RAMPs (receptor-activity-modifying proteins) and RASSLs (receptor activated solely by synthetic ligands); (ii) AGS (activators of G protein signaling) and RGS (regulators of G protein signaling) proteins which modify G protein activity; (iii) the high diversity of isozymes involved in the generation, signal transmission, and degradation of second messenger molecules.
Animals↗