Patients with myeloproliferative neoplasms (MPNs) suffer from often debilitating constitutional symptoms that negatively impact quality of life to a degree similar to patients with metastatic solid ...tumors. Despite heterogeneity in the breadth and severity of symptoms in MPNs, research into symptom assessment has led to the creation of well validated patient reported outcome tools, including the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Currently available pharmacologic therapies, particularly JAK inhibitors, result in substantial reduction in symptom burden for patients with myelofibrosis, as well as select patient with polycythemia vera and essential thrombocythemia. Non-pharmacologic therapies including yoga and meditation have also been investigated. In this review, we focus on the pathogenesis and assessment of constitutional symptoms in MPNs. We detail currently available therapies to address symptom burden and highlight several novel agents in development. We end by discussing unmet needs and exploring the future of symptom assessment and treatment in MPNs.
Emerging therapies for atopic dermatitis: JAK inhibitors Cotter, David G.; Schairer, David; Eichenfield, Lawrence
Journal of the American Academy of Dermatology,
March 2018, 2018-03-00, 20180301, Letnik:
78, Številka:
3
Journal Article
Recenzirano
The Janus kinase–signal transducer and activator of transcription pathway is a conserved master regulator of immunity and myeloproliferation. Advanced understanding of this pathway has led to ...development of targeted inhibitors of Janus kinases (Jakinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Given such success, use of JAK inhibitors for mitigation of atopic dermatitis is under active investigation. Herein, we review the evolving data on the safety and efficacy of JAK inhibitors in treatment of atopic dermatitis. Although it is still early in the study of JAK inhibitors for atopic dermatitis, evidence identifies JAK inhibitors as effective alternatives to conventional therapies. Nonetheless, multiple large safety and efficacy trials are needed before widespread use of JAK inhibitors can be advocated for atopic dermatitis.
Atopic dermatitis is a chronic recurring pruritic inflammatory skin disease manifested by increased pro-inflammatory mediators which lead to dry, thickened, cracked, scaly skin. The current treatment ...options for atopic dermatitis management comprise drawbacks and leave unmet effective clinical needs. So, the approach for repurposing existing drugs for atopic dermatitis management may potentially overcome these unmet needs. Diseases that share the common pathophysiological pathways with atopic dermatitis can serve as a foundation for the repurposing of drugs. Drugs used in the management of cancer, rheumatoid arthritis, and other immune-mediated diseases such as psoriasis are under investigation to know the potential in atopic dermatitis management by utilizing repurposing strategies for a novel therapeutic indication. This review mainly envisages the probable repurposing of drugs for the management of atopic dermatitis disease; the barriers and regulatory aspects involved in the repurposing of existing drugs.
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•Atopic dermatitis, a chronic recurring pruritic inflammatory skin disease manifested by increased pro-inflammatory mediators.•Safety issues with current therapies are tachyphylaxis, skin atrophy, skin thinning, lymphoma, skin cancer, etc.•Drug repurposing offers a new therapeutic option to overcome the safety concerns of current therapies in atopic dermatitis.•Potential drugs for repurposing includes inhibitors JAK-STAT pathway, immune-mediated factors and inflammatory cytokines.
Overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET (Bromodomain and ...extraterminal domain family) bromodomain (BRDs) inhibitor, has been found to suppress tumour progression in several cancer cell types.
Using a panel of ovarian cancer cell lines and primary cell cultures from human ovarian cancer ascites, we demonstrated that JQ1 significantly suppressed cell proliferation and induced apoptosis in an ovarian cancer cell by targeting BRD4 and c-Μyc. In addition, JQ1 sensitized ovarian cancer cells to cisplatin, the most commonly used chemotherapeutic agent in ovarian cancer. Importantly, this effect was observed in ovarian cells, which exhibited resistance to cisplatin alone. Finally, we show that JQ1 interacts with the JAK-STAT signalling pathway, a pathway important in supporting ovarian cancer cell survival by suppressing or inducing genes involved in cell survival and apoptosis, respectively.
Our data, taken together, suggest that JQ1 is an attractive antitumour candidate for further investigation in the treatment of ovarian cancer, as it associates with cell proliferation, apoptosis, and alterations in the JAK-STAT signalling pathway, especially in patients with a platinum-resistant profile or in patients with relapsed disease.
•JQ1 suppresses cell survival and induces apoptosis in ovarian cancer by targeting BRD4 and c-Μyc.•JQ1 demonstrates antisurvival effects in ovarian cells, which exhibit resistance to cisplatin.•JQ1 interacts with JAK-STAT pathway by differentiating genes involved in survival and apoptosis.
Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine ...pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480-but not a JAK1/JAK3 selective inhibitor, tofacitinib-also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.
Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T‐cell lineage acute lymphoblastic leukemia (T‐ALL). However, the roles played by ...suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T‐ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T‐ALL and its expression levels were lowered in HOXA‐deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase‐3A‐mediated DNA methylation and methyl CpG binding protein‐2‐mediated histone deacetylation. We show that SOCS5 negatively regulates T‐ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK‐STAT signaling, and negatively regulates interleukin‐7 and interleukin‐4 receptors. Using a human T‐ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T‐ALL and serves as an important regulator of T‐ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK‐STAT and cytokine receptor‐signaling cascade in T‐ALL.
Suppressor of cytokine signaling 5 (SOCS5) is differentially expressed in T‐cell lineage acute lymphoblastic leukemia (T‐ALL), and its expression levels are lowered in HOXA‐deregulated leukemia harboring KMT2A gene rearrangements. SOCS5 is epigenetically regulated by DNA methyltransferase‐3A‐mediated DNA methylation and methyl CpG binding protein‐2‐mediated histone deacetylation. Epigenetic silencing of SOCS5 potentiates interleukin‐7 receptor/JAK‐STAT signal transduction and T‐ALL progression.
Atherosclerosis is a chronic inflammatory disease of the blood vessels, characterized by atherosclerotic lesion formation. Vascular Smooth Muscle Cells (VSMC), macrophages (MΦ), and dendritic cells ...(DC) play a crucial role in vascular inflammation and atherosclerosis. Interferon (IFN)α, IFNγ, and Toll-like receptor (TLR)4 activate pro-inflammatory gene expression and are pro-atherogenic. Gene expression regulation of many pro-inflammatory genes has shown to rely on Signal Integration (SI) between IFNs and TLR4 through combinatorial actions of the Signal Transducer and Activator of Transcription (STAT)1 complexes ISGF3 and γ-activated factor (GAF), and Nuclear Factor-κB (NFκB). Thus, IFN pre-treatment ("priming") followed by LPS stimulation leads to enhanced transcriptional responses as compared to the individual stimuli. To characterize the mechanism of priming-induced IFNα + LPS- and IFNγ + LPS-dependent SI in vascular cells as compared to immune cells, we performed a comprehensive genome-wide analysis of mouse VSMC, MΦ, and DC in response to IFNα, IFNγ, and/or LPS. Thus, we identified IFNα + LPS or IFNγ + LPS induced genes commonly expressed in these cell types that bound STAT1 and p65 at comparable γ-activated sequence (GAS), Interferon-stimulated response element (ISRE), or NFκB sites in promoter proximal and distal regions. Comparison of the relatively high number of overlapping ISRE sites in these genes unraveled a novel role of ISGF3 and possibly STAT1/IRF9 in IFNγ responses. In addition, similar STAT1-p65 co-binding modes were detected for IFNα + LPS and IFNγ + LPS up-regulated genes, which involved recruitment of STAT1 complexes preceding p65 to closely located GAS/NFκB or ISRE/NFκB composite sites already upon IFNα or IFNγ treatment. This STAT1-p65 co-binding significantly increased after subsequent LPS exposure and correlated with histone acetylation, PolII recruitment, and amplified target gene transcription in a STAT1-p65 co-bound dependent manner. Thus, co-binding of STAT1-containing transcription factor complexes and NFκB, activated by IFN-I or IFN-II together with LPS, provides a platform for robust transcriptional activation of pro-inflammatory genes. Moreover, our data offer an explanation for the comparable effects of IFNα or IFNγ priming on TLR4-induced activation in vascular and immune cells, with important implications in atherosclerosis.
Introduction: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, ...Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors.
Areas covered: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years.
Expert opinion: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.
ABSTRACT
Viruses use a spectrum of immune evasion strategies that enable infection and replication. The acute phase of hepatitis C virus (HCV) infection is characterized by nonspecific and often mild ...clinical symptoms, suggesting an immunosuppressive mechanism that, unless symptomatic liver disease presents, allows the virus to remain largely undetected. We previously reported that HCV induced the regulatory protein suppressor of cytokine signaling (SOCS)3, which inhibited TNF‐α‐mediated inflammatory responses. However, the mechanism by which HCV up‐regulates SOCS3 remains unknown. Here we show that the HCV protein, p7, enhances both SOCS3 mRNA and protein expression. A p7 inhibitor reduced SOCS3 induction, indicating that p7′s ion channel activity was required for optimal up‐regulation of SOCS3. Short hairpin RNA and chemical inhibition revealed that both the Janus kinase–signal transducer and activator of transcription (JAK‐STAT) and MAPK pathways were required for p7‐mediated induction of SOCS3. HCV‐p7 expression suppressed TNF‐α‐mediated IκB‐α degradation and subsequent NF‐κB promoter activity, revealing a new and functional, anti‐inflammatory effect of p7. Together, these findings identify a molecular mechanism by which HCV‐p7 induces SOCS3 through STAT3 and ERK activation and demonstrate that p7 suppresses proinflammatory responses to TNF‐α, possibly explaining the lack of inflammatory symptoms observed during early HCV infection.—Convery, O., Gargan, S., Kickham, M., Schroder, M., O'Farrelly, C., Stevenson, N. J. The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)‐α via signal transducer and activator of transcription (STAT)3 and extracellular signal‐regulated kinase (ERK)–mediated induction of suppressor of cytokine signaling (SOCS)3. FASEB J. 33, 8732–8744 (2019). www.fasebj.org
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