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Ruxolitinib

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https://www.readbyqxmd.com/read/29228628/drug-sensitivity-profiling-identifies-potential-therapies-for-lymphoproliferative-disorders-with-overactive-jak-stat3-signaling
#1
Heikki Kuusanmäki, Olli Dufva, Elina Parri, Arjan J van Adrichem, Hanna Rajala, Muntasir M Majumder, Bhagwan Yadav, Alun Parsons, Wing C Chan, Krister Wennerberg, Satu Mustjoki, Caroline A Heckman
Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228564/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#2
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29226717/atypical-chronic-myeloid-leukemia-a-rare-entity-with-management-challenges
#3
Prajwal Dhakal, Krishna Gundabolu, Catalina Amador, Supratik Rayamajhi, Vijaya Raj Bhatt
The aim of our study was to review the clinicopathologic features and management of atypical chronic myeloid leukemia (aCML). Relevant manuscripts published in English were searched using PubMed. aCML is diagnosed as per WHO 2016 classification in the presence of leukocytosis ≥13 × 109/l with circulating neutrophil precursors ≥10%, monocytes less than 10%, minimal basophils, hypercellular bone marrow with granulocytic proliferation and dysplasia, bone marrow blast less than 20% and absence of BCR/ABL fusion gene...
December 11, 2017: Future Oncology
https://www.readbyqxmd.com/read/29226168/risks-of-ruxolitinib-in-stat1-gain-of-function-associated-severe-fungal-disease
#4
Ofer Zimmerman, Berenice Rösler, Christa S Zerbe, Lindsey B Rosen, Amy P Hsu, Gulbu Uzel, Alexandra F Freeman, Elizabeth P Sampaio, Sergio D Rosenzwieg, Hye Sun Kuehn, Tiffany Kim, Kristina M Brooks, Parag Kumar, Xiaowen Wang, Mihai G Netea, Frank L van de Veerdonk, Steven M Holland
Heterozygous STAT1 gain-of-function (GOF) mutations are associated with chronic mucocutaneous candidiasis and a broad spectrum of infectious, inflammatory, and vascular manifestations. We describe therapeutic failures with the Janus Kinase (JAK) inhibitor ruxolitinib in 2 STAT1 GOF patients with severe invasive or cutaneous fungal infections.
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/29224367/effect-of-ruxolitinib-therapy-on-the-quality-of-life-of-japanese-patients-with-myelofibrosis
#5
Kenji Oritani, Kohshi Ohishi, Shinichiro Okamoto, Keita Kirito, Norio Komatsu, Tetsuzo Tauchi, Hiroshi Handa, Shigeki Saito, Katsuto Takenaka, Kazuya Shimoda, Hikaru Okada, Taro Amagasaki, Shiho Wakase, Kojiro Shimozuma, Koichi Akashi
OBJECTIVES: Myelofibrosis (MF) is associated with a significant symptom burden that severely impacts patient quality of life (QOL). Ruxolitinib, a potent Janus kinase 1 (JAK1)/JAK2 inhibitor, led to substantial improvements in splenomegaly, MF-associated symptoms, and QOL in the phase 3 COMFORT studies, proving superior to placebo and best available therapy. We evaluated the effect of ruxolitinib on symptoms and QOL in Japanese patients with MF. METHODS: We conducted a pooled analysis of studies A2202 (NCT01392443) and AJP01 (NCT02087059) of ruxolitinib in Japanese patients with MF (N = 81)...
December 9, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/29222296/what-are-the-current-treatment-approaches-for-patients-with-polycythemia-vera-and-essential-thrombocythemia
#6
REVIEW
Alessandro M Vannucchi, Paola Guglielmelli
Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the "state of the art" in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29220734/high-throughput-routine-determination-of-17-tyrosine-kinase-inhibitors-by-lc-ms-ms
#7
Camille Merienne, Marine Rousset, Dominique Ducint, Nadège Castaing, Karine Titier, Mathieu Molimard, Stéphane Bouchet
Several studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKI) can improve their benefit in cancer. An analytical tool has been developed in order to quantify 17 tyrosine kinase inhibitors and 2 metabolites in human plasma (afatinib, axitinib, bosutinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, ponatinib, regorafenib, regorafenib M2, regorafenib M5, ruxolitinib, sorafenib, sunitinib, vandetanib). Drugs were arranged in four groups, according to their plasma concentration range: 0...
November 28, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29214116/compassionate-use-of-ruxolitinib-in-acute-and-chronic-graft-versus-host-disease-refractory-both-to-corticosteroids-and-extracorporeal-photopheresis
#8
Mauricio Sarmiento Maldonado, Pablo Ramírez Villanueva, Pablo Bertín Cortes-Monroy, Veronica Jara Arias, Katherine Soto Donoso, Pablo Uribe Gonzalez, Mauricio Ocqueteau Tachini, Jose Antonio Perez-Simón
Background: Ruxolitinib is a potent inhibitor of JAK1/2 with proven efficacy in myelofibrosis. In recent years, research in graft versus host disease (GVHD) has revealed the role of activation of JAK pathways in alloreactive lymphocytes. Some reports have shown significant responses in refractory GVHD patients. Cases presentation: In this report we present our experience in 8 patients with acute or chronic GVHD with refractoriness to steroids and extracorporeal photopheresis treated with ruxolitinib...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29212208/ruxolitinib-sensitizes-ovarian-cancer-to-reduced-dose-taxol-limits-tumor-growth-and-improves-survival-in-immune-competent-mice
#9
Patrick M Reeves, Mojgan A Abbaslou, Farah R W Kools, Kritchai Vutipongsatorn, Xiaoyun Tong, Christina Gavegano, Raymond F Schinazi, Mark C Poznansky
Background: Chemotherapy initially reduces the tumor burden in patients with ovarian cancer. However, tumors recur in over 70% of patients, creating the need for novel therapeutic approaches. Methods: We evaluated Ruxolitinib, an FDA-approved JAK 1/2 kinase inhibitor, as a potential adjunctive therapy for use with low-dose Taxol (Paclitaxel) by assessing the impact on in vitro proliferation and colony formation of ID8 cells or human TOV-112D ovarian cancer cells, as well as flow cytometric measurement of surface markers associated with cellular stress and stemness by ID8 cells...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207662/tumor-associated-macrophages-promote-neuroblastoma-via-stat3-phosphorylation-and-up-regulation-of-c-myc
#10
Michael D Hadjidaniel, Sakunthala Muthugounder, Long T Hung, Michael A Sheard, Soheila Shirinbak, Randall Y Chan, Rie Nakata, Lucia Borriello, Jemily Malvar, Rebekah J Kennedy, Hiroshi Iwakura, Takashi Akamizu, Richard Sposto, Hiroyuki Shimada, Yves A DeClerck, Shahab Asgharzadeh
Tumor-associated macrophages (TAMs) are strongly associated with poor survival in neuroblastomas that lack MYCN amplification. To study TAM action in neuroblastomas, we used a novel murine model of spontaneous neuroblastoma lacking MYCN amplification, and observed recruitment and polarization of TAMs, which in turn enhanced neuroblastoma proliferation and growth. In both murine and human neuroblastoma cells, we found that TAMs increased STAT3 activation in neuroblastoma cells and transcriptionally up-regulated the MYC oncogene...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29203240/il-13-regulates-il-17c-expression-by-suppressing-nf-%C3%AE%C2%BAb-mediated-transcriptional-activation-in-airway-epithelial-cells
#11
Katsumasa Yamanaka, Tomoyuki Fujisawa, Hideki Kusagaya, Kazutaka Mori, Mitsuru Niwa, Kazuki Furuhashi, Masato Kono, Etsuko Hamada, Takafumi Suda, Masato Maekawa
The cytokine interleukin (IL)-17C is highly expressed in epithelial tissues and involved in innate immune responses; however, the regulation of IL-17C expression in the airways remains poorly understood. Here, we show that IL-1β strongly induces both IL-17C mRNA and protein expression in primary normal human bronchial epithelial cells. Conversely, IL-13 significantly reduced the IL-1β-induced IL-17C expression. Attenuation of the nuclear factor (NF)-κB-signaling pathway using an NF-κB-subunit p65-specific small-interfering RNA (siRNA), reduced IL-1β-induced IL-17C expression, demonstrating the importance of NF-κB signaling in IL-17C regulation...
December 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29202476/stromal-lkb1-deficiency-leads-to-gastrointestinal-tumorigenesis-involving-the-il-11-jak-stat3-pathway
#12
Saara Ollila, Eva Domènech-Moreno, Kaisa Laajanen, Iris Pl Wong, Sushil Tripathi, Nalle Pentinmikko, Yajing Gao, Yan Yan, Elina H Niemelä, Timothy C Wang, Benoit Viollet, Gustavo Leone, Pekka Katajisto, Kari Vaahtomeri, Tomi P Mäkelä
Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma...
December 4, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29202299/repression-of-interferon-%C3%AE-regulated-cytokines-by-the-jak1-2-inhibitor-ruxolitinib-in-inflammatory-human-macrophages
#13
Marie Febvre-James, Valérie Lecureur, Yu Augagneur, Abdullah Mayati, Olivier Fardel
Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point, ruxolitinib effects towards expression of main inflammatory cytokines were studied in human macrophages, which constitute a key-cell type implicated in inflammation. Analysis of mRNA expression of cytokines (n=84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus lipopolysaccharide (LPS) (n=44), 61...
December 1, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29196988/analysis-of-spontaneous-postmarket-case-reports-submitted-to-the-fda-regarding-thromboembolic-adverse-events-and-jak-inhibitors
#14
Abril Verden, Mo Dimbil, Robert Kyle, Brian Overstreet, Keith B Hoffman
INTRODUCTION: The Janus kinase (JAK) inhibitor baricitinib is approved in Europe and Japan for the treatment of rheumatoid arthritis. In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis [DVT] and pulmonary embolism [PE]) observed in placebo-controlled clinical trials of baricitinib. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk. Given that the FDA-approved drugs tofacitinib and ruxolitinib are in the same class, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess postmarketing reporting rates for related thromboembolic risks...
December 2, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/29189896/between-a-rux-and-a-hard-place-evaluating-salvage-treatment-and-outcomes-in-myelofibrosis-after-ruxolitinib-discontinuation
#15
Andrew T Kuykendall, Savan Shah, Chetasi Talati, Najla Al Ali, Kendra Sweet, Eric Padron, David A Sallman, Jeffrey E Lancet, Alan F List, Kenneth S Zuckerman, Rami S Komrokji
Ruxolitinib is a JAK1/2 inhibitor that is effective in managing symptoms and splenomegaly related to myelofibrosis (MF). Unfortunately, many patients must discontinue ruxolitinib, at which time treatment options are not well defined. In this study, we investigated salvage treatment options and clinical outcomes among MF patients who received and discontinued ruxolitinib outside the context of a clinical trial. Among 145 patients who received ruxolitinib, 23 died while on treatment, 58 remained on treatment at time of analysis, leaving 64 people available for analysis...
November 30, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29171774/advances-in-treating-psoriasis-in-the-elderly-with-small-molecule-inhibitors
#16
Abigail Cline, Leah A Cardwell, Steven R Feldman
Due to the chronic nature of psoriasis, the population of elderly psoriasis patients is increasing. However, many elderly psoriatic patients are not adequately treated because management is challenging as a result of comorbidities, polypharmacy, and progressive impairment of organ systems. Physicians may hesitate to use systemic or biologic agents in elderly psoriasis patients because of an increased risk of adverse events in this patient population. Small molecule medications are emerging as promising options for elderly patients with psoriasis and other inflammatory conditions...
November 24, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29163799/jak2-aberrations-in-childhood-b-cell-precursor-acute-lymphoblastic-leukemia
#17
Elisabeth M P Steeghs, Isabel S Jerchel, Willemieke de Goffau-Nobel, Alex Q Hoogkamer, Judith M Boer, Aurélie Boeree, Cesca van de Ven, Marco J Koudijs, Nicolle J M Besselink, Hester A de Groot-Kruseman, Christian Michel Zwaan, Martin A Horstmann, Rob Pieters, Monique L den Boer
JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions)...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29162613/the-jak1-2-inhibitor-ruxolitinib-reverses-interleukin-6-mediated-suppression-of-drug-detoxifying-proteins-in-cultured-human-hepatocytes
#18
Marie Febvre-James, Arnaud Bruyere, Marc Le Vee, Olivier Fardel
The inflammatory cytokine interleukin (IL)-6, which basically activates the JAK/STAT signaling pathway, is well-known to repress expression of hepatic cytochromes P-450 (CYPs) and transporters. Therapeutic proteins, like mAbs targeting IL-6 or its receptor, have been consequently demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract IL-6 repressing effects towards hepatic detoxifying systems...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29150886/ruxolitinib-associated-infections-a-systematic-review-and-meta-analysis
#19
Federico Lussana, Marco Cattaneo, Alessandro Rambaldi, Alessandro Squizzato
Ruxolitinib exerts immunosuppressive activity that may increase the risk of infectious complications. We performed a systematic review of the literature with the aim of estimating the risk of infections in patients treated with ruxolitinib. Studies were identified by electronic search of MEDLINE and EMBASE database. Differences in the incidence of infectious events between ruxolitinib and comparison groups were expressed as odds ratios (ORs) and 95% confidence intervals (95% CI). Five phase III randomized clinical trials (RCTs) (3 phase IIIa with their extended phase and 2 phase IIIb), 6 phase IV studies and 28 case reports were included in this systematic review...
November 18, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29150291/ruxolitinib-conjugated-gold-nanoparticles-for-topical-administration-an-alternative-for-treating-alopecia
#20
Sanda Boca, Cristian Berce, Ancuta Jurj, Bobe Petrushev, Laura Pop, Grigore-Aristide Gafencu, Sonia Selicean, Vlad Moisoiu, Daiana Temian, Wilhelm-Thomas Micu, Simion Astilean, Cornelia Braicu, Ciprian Tomuleasa, Ioana Berindan-Neagoe
Alopecia is a dermatological condition for which Janus kinase (JAK) inhibitors have recently emerged as potential therapy options, but with limited practical use because of the systemic side effects. The topical use of Ruxolitinib in alopecia universalis has been demonstrated, but little is known about the pharmacodynamics and pharmacokinetics of this way of administration. Nanomedicine provides improved therapeutics. In the current paper we present preliminary data regarding the potential use of Ruxolitinib-conjugated gold nanoparticles (GNPs) in dermatological conditions, as GNPs have been proven to have a reduced absorption rate into the systemic blood flow for cutaneous administration...
November 2017: Medical Hypotheses
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