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Expert Opinion on Therapeutic Targets

Kinji Ohno, Bisei Ohkawara, Mikako Ito
Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, congenital myasthenic syndromes, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Except for sarcopenia, all are orphan diseases. In addition, the NMJ signal transduction is impaired by tetanus, botulinum, curare, α-bungarotoxin, conotoxins, organophosphate, sarin, VX, and soman to name a few...
August 21, 2017: Expert Opinion on Therapeutic Targets
Kohji Moriishi
Chronic infection with hepatitis C virus (HCV) causes liver steatosis, cirrhosis, metabolic syndrome with inflammation, and eventually leads to hepatocellular carcinoma. HCV core protein is a well-known capsid protein and pathogenic factor related to lipid accumulation, type 2 diabetes mellitus, and carcinogenesis. Cleavage of the C-terminal transmembrane region by signal peptide peptidase (SPP) is required for maturation of the core protein. Areas covered: Herein, this review details the general aspects of the structure, lifecycle, pathogenesis, and maturation of the HCV core protein, the function of SPP, and clinically available direct-acting antivirals (DAAs)...
August 18, 2017: Expert Opinion on Therapeutic Targets
Ju-Ha Kim, Hyemin Lee, Eun Ah Shin, Dong Hee Kim, Jhin Baek Choi, Sung-Hoon Kim
Among several genetic alterations involved in the progression of prostate cancer, B cell lymphoma gene number 2 (BCL-2) is an important target molecule in the progression of androgen-independent prostate cancer (AIPC) after androgen ablation or castration. Nevertheless, the molecular mechanism of BCL-2 in prostate cancer progression remains elusive and controversial. In the current review, we discuss the critical role of BCL-2 in the carcinogenesis of prostate cancer with experimental evidences on the BCL-2 molecular networks in AIPC and androgen-dependent prostate cancer (ADPC) and subsequently suggest perspective research targeting BCL-2...
August 17, 2017: Expert Opinion on Therapeutic Targets
Mary Kathryn Pitner, Juliana M Taliaferro, Kevin N Dalby, Chandra Bartholomeusz
There is an unmet need in triple-negative breast cancer (TNBC) patients for targeted therapies. Maternal embryonic leucine zipper kinase (MELK) is a promising target for inhibition based on the abundance of correlative and functional data supporting its role in various cancer types. Areas covered: This review endeavors to outline the role of MELK in cancer. Studies covering a range of biological functions including proliferation, apoptosis, cancer stem cell phenotypes, epithelial-to-mesenchymal transition, metastasis, and therapy resistance are discussed here in order to understand the potential of MELK as a clinically significant target for TNBC patients...
August 16, 2017: Expert Opinion on Therapeutic Targets
Lidia Ruiz-Llorente, Eunate Gallardo-Vara, Elisa Rossi, David M Smadja, Luisa M Botella, Carmelo Bernabeu
Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level...
August 10, 2017: Expert Opinion on Therapeutic Targets
Luiza Oliveira Perucci, Michelle Amantéa Sugimoto, Karina Braga Gomes, Luci Maria Dusse, Mauro Martins Teixeira, Lirlândia Pires Sousa
The timely resolution of inflammation is essential to restore tissue homeostasis and to avoid chronic inflammatory diseases. Resolution of inflammation is an active process modulated by various proresolving mediators, including annexin A1 (AnxA1) and specialized proresolving lipid mediators (SPMs), which counteract excessive inflammatory responses and stimulate proresolving mechanisms. Areas covered: The protective effects of AnxA1 and SPMs have been extensively explored in pre-clinical animal models. However, studies investigating the function of these molecules in human diseases are just emerging...
August 8, 2017: Expert Opinion on Therapeutic Targets
Adeline Sivignon, Julie Bouckaert, Julien Bernard, Sebastien G Gouin, Nicolas Barnich
Crohn's disease (CD) is a life-long chronic disorder characterized by intestinal inflammation. Current treatments for CD are directed towards abnormal immune responses rather than the intestinal bacteria that trigger intestinal inflammation. Areas covered: Adherent-Invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa in a subgroup of CD patients. They can promote or perpetuate chronic inflammation and are therefore an interesting therapeutic target. Various strategies that target these E...
August 1, 2017: Expert Opinion on Therapeutic Targets
Laura Rosanò, Roberta Cianfrocca, Rosanna Sestito, Piera Tocci, Valeriana Di Castro, Anna Bagnato
Endothelin-1 receptor (ET-1R)/β-arrestin1 (β-arr1) signaling is dysregulated in ovarian cancer. This signaling circuit enables cancer cells to engage several signaling and transcriptional networks that are pervasively intertwined, and represent a potential therapeutic target for developing novel agents for ovarian cancer treatment. Areas covered: In this article, we discuss the role of the signaling network between ET-1R and key pathways mediated by the scaffold protein β-arr1, as part of signaling complex, or as a transcription co-activator, promoting precise control of transcription of different genes, including ET-1...
July 31, 2017: Expert Opinion on Therapeutic Targets
Davide Randazzo, Enrico Pierantozzi, Daniela Rossi, Vincenzo Sorrentino
Obscurin, a giant protein of striated muscles, is emerging as an important player in a wide range of processes including myofibril assembly and maintenance, muscle protein degradation and intracellular signaling. Accordingly, obscurin participates to the mechanisms by which muscles adapt to physiological requirements or to pathological cues associated with cardiac and skeletal muscle diseases. Areas covered: The structure of the different obscurin isoforms identified so far, their tissue distribution and the most recent findings on obscurin in invertebrates and mammals will be reviewed...
July 29, 2017: Expert Opinion on Therapeutic Targets
Susanna Cogo, Elisa Greggio, Patrick A Lewis
No abstract text is available yet for this article.
June 22, 2017: Expert Opinion on Therapeutic Targets
Jo Nijs, Marco L Loggia, Andrea Polli, Maarten Moens, Eva Huysmans, Lisa Goudman, Mira Meeus, Luc Vanderweeën, Kelly Ickmans, Daniel Clauw
The mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available...
August 2017: Expert Opinion on Therapeutic Targets
Jinwei Zhang, Jason K Karimy, Eric Delpire, Kristopher T Kahle
The mammalian SPS1-related proline/alanine-rich serine-threonine kinase SPAK (STK39) modulates ion transport across and between epithelial cells in response to environmental stimuli such osmotic stress and inflammation. Research over the last decade has established a central role for SPAK in the regulation of ion and water transport in the distal nephron, colonic crypts, and pancreatic ducts, and has implicated deregulated SPAK signaling in NaCl-sensitive hypertension, ulcerative colitis and Crohn's disease, and cystic fibrosis...
August 2017: Expert Opinion on Therapeutic Targets
Elena Catanzaro, Cinzia Calcabrini, Eleonora Turrini, Piero Sestili, Carmela Fimognari
Nuclear factor (erythroid-derived-2)-like 2 is one of the most efficient cytoprotective rheostats against exogenous or endogenous oxidative insults. At present, the modulation of the Nrf2 pathway represents an interesting and highly explored strategy in the oncological area. Area covered: In this review, we present and discuss the different modulation of the Nrf2 pathway by some natural compounds with a well demonstrated anticancer activity, and critically analyze the challenges associated with the development of an Nrf2-based anticancer strategy...
August 2017: Expert Opinion on Therapeutic Targets
Luis Molina, Carlos D Figueroa, Kanti D Bhoola, Pamela Ehrenfeld
Breast cancer is clinically classified as 'estrogen-positive' when at least 1% of cancer cells stain for the estrogen receptor alpha (ERα). However, recent research on both basic and clinical aspects of breast cancer suggests that GPER-1 (G protein-coupled estrogen receptor-1) may have an important role in breast cancer. Areas covered: This review provides a comprehensive and systematic literature search on GPER-1. We have focused on the role of GPER-1 in breast cancer and on resistance to endocrine therapy, an unsolved clinical issue still under discussion...
August 2017: Expert Opinion on Therapeutic Targets
Jeroen E Guikema, Martine Amiot, Eric Eldering
Direct targeting of Bcl-2 members for therapeutic purposes in cancer has become a clinical reality with the FDA approval of ABT-199/Venetoclax. Other highly specific BH3-mimetics are in pre-clinical development. Understanding the functional interactions among the Bcl-2 family is of prime importance to fully exploit their potential. NOXA is considered a rather weak BH3-only member but it has unexplored potential in various settings, which are of relevance in cancer. NOXA is best known as a selective inhibitor of MCL1, itself overexpressed in many cancers, and this protein pair forms an important rheostat in many forms of cell stress...
August 2017: Expert Opinion on Therapeutic Targets
Giacomo Lettini, Francesca Maddalena, Lorenza Sisinni, Valentina Condelli, Danilo Swann Matassa, Maria Paola Costi, Daniele Simoni, Franca Esposito, Matteo Landriscina
HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors. Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells...
August 2017: Expert Opinion on Therapeutic Targets
Pathricia V Tilstam, Dake Qi, Lin Leng, Lawrence Young, Richard Bucala
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia...
July 2017: Expert Opinion on Therapeutic Targets
Shi-Yang Guan, Rui-Xue Leng, Jin-Hui Tao, Xiang-Pei Li, Dong-Qing Ye, Nancy Olsen, Song Guo Zheng, Hai-Feng Pan
Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1α is associated with the inflammation and pathologic activities of autoimmune diseases. Areas covered: Considering that the types of autoimmune diseases are complicated and various, this review aims to cover the typical kinds of autoimmune diseases, discuss the molecular mechanisms, biological functions and expression of HIF-1α in these diseases, and further explore its therapeutic potential...
July 2017: Expert Opinion on Therapeutic Targets
Man-Hsin Hung, Kuen-Feng Chen
SET is a multitask oncoprotein that promotes the initiation and progression of cancer. Overexpression of SET has been characterized as being tumor-specific and is associated with adverse clinical outcomes in many different human malignant diseases. Notably, SET has been shown to promote the development of therapeutic resistance in cancer cells. Area covered: In this review, we summarized the currently available evidence relating to the oncogenic roles, biological functions and clinical relevance of SET protein in cancer...
July 2017: Expert Opinion on Therapeutic Targets
Yoko Tabe, Agostino Tafuri, Kazumasa Sekihara, Haeun Yang, Marina Konopleva
Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML. Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival...
July 2017: Expert Opinion on Therapeutic Targets
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