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Mehrad Tavallai, Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
We determined whether the approved myelofibrosis drug ruxolitinib (Jakafi(®)), an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could be repurposed as an anti-cancer agent for solid tumors. Ruxolitinib synergistically interacted with dual ERBB1/2/4 inhibitors to kill breast as well as lung, ovarian and brain cancer cells. Knock down of JAK1/2 or of ERBB1/2/3/4 recapitulated on-target drug effects. The combination of (ruxolitinib + ERBB1/2/4 inhibitor) rapidly inactivated AKT, mTORC1, mTORC2, STAT3, and STAT5, and activated eIF2α...
2016: Frontiers in Oncology
Lisa A Raedler
No abstract text is available yet for this article.
March 2015: American Health & Drug Benefits
Kate McKeage
Ruxolitinib (Jakavi(®), Jakafi(®)) is an orally administered, first-in-class Janus Kinase (JAK) 1 and 2 inhibitor that was recently approved for the treatment of patients with polycythaemia vera (PV) who have responded inadequately to or are intolerant of hydroxyurea. By inhibiting JAK 1 and 2, ruxolitinib reduces hyperactive JAK-signal transducers and activators of transcription (STAT) signalling that is implicated in the pathogenesis of PV. This article briefly reviews the pharmacology of the drug, focusing on its clinical use in patients with PV...
October 2015: Drugs
Greg L Plosker
Ruxolitinib (Jakavi(®), Jakafi(®)) is an orally administered inhibitor of Janus kinases (JAK) 1 and 2 used in the management of patients with myelofibrosis. Clinical trials with ruxolitinib, notably the phase III COMFORT-I and -II studies and their extensions, have demonstrated marked and durable clinical benefits in terms of reductions in splenomegaly and disease-related symptoms in patients with intermediate-2 or high-risk myelofibrosis. Ruxolitinib was also associated with improvements in health-related quality of life and functioning...
February 2015: Drugs
Muhammad Furqan, Nikhil Mukhi, Byung Lee, Delong Liu
JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS)...
2013: Biomarker Research
Claire Harrison, Ruben Mesa, David Ross, Adam Mead, Clodagh Keohane, Jason Gotlib, Srdan Verstovsek
Myelofibrosis (MF) is characterized by bone marrow fibrosis, progressive anemia and extramedullary hematopoiesis, primarily manifested as splenomegaly. Patients also experience debilitating constitutional symptoms, including sequelae of splenomegaly, night sweats and fatigue. Ruxolitinib (INC424, INCB18424, Jakafi, Jakavi), a JAK1 and JAK2 inhibitor, was approved in November 2011 by the US FDA for the treatment of intermediate- or high-risk MF, and more recently in Europe and Canada for the treatment of MF-related splenomegaly or symptoms...
October 2013: Expert Review of Hematology
Karoline Gäbler, Iris Behrmann, Claude Haan
The Janus kinase 2 (JAK2) mutant V617F and other JAK mutants are found in patients with myeloproliferative neoplasms and leukemias. Due to their involvement in neoplasia and inflammatory disorders, Janus kinases are promising targets for kinase inhibitor therapy. Several small-molecule compounds are evaluated in clinical trials for myelofibrosis, and ruxolitinib (INCB018424, Jakafi®) was the first Janus kinase inhibitor to receive clinical approval. In this review we provide an overview of JAK2V617F signaling and its inhibition by small-molecule kinase inhibitors...
July 1, 2013: JAK-STAT
D Escobar-Zarate, Y-P Liu, L Suksanpaisan, S J Russell, K-W Peng
Oncolytic vesicular stomatitis virus (VSV) has potent antitumor activity but some cancer cells are resistant to VSV killing, either constitutively or due to type I interferon (IFN) inducing an antiviral state in the cells. Here, we evaluated VSV oncolysis of a panel of human head and neck cancer cells and showed that VSV resistance in SCC25 and SCC15 cells could be reversed with Janus kinase (JAK) 1/2 inhibitors (JAK inhibitor I and ruxolitinib). Pre-treatment of cells with JAK1/2 inhibitors before or in conjunction with VSV enhanced viral infection, spread and progeny yield (100- to 1000-fold increase)...
October 2013: Cancer Gene Therapy
Marina Kremyanskaya, Ehab L Atallah, Ronald Hoffman, John O Mascarenhas
Myelofibrosis (MF) is a hematopoietic stem cell malignancy classified as a myeloproliferative neoplasm (MPN). The clinical course of individuals with MF is heterogeneous and characterized by constitutional symptoms, bone marrow myeloproliferation and fibrosis, progressive cytopenias, and symptomatic splenomegaly. Historically, patients with this debilitating disease have had limited treatment options, and disease-modifying agents were not available. Hematopoietic stem cell transplantation is the only potentially curative therapy, but it is only an option for select patients...
July 2013: Oncology (Williston Park, NY)
Victoria K Shanmugam, Sean McNish, Nawar Shara, Katherine J Hubley, Bhaskar Kallakury, David M Dunning, Christopher E Attinger, John S Steinberg
We present the case of a 63-year-old white male with bilateral chronic leg ulcers due to polycythemia vera and hydroxyurea therapy who demonstrated dramatic healing of his wounds in response to ruxolitinib (Jakafi(®), Novartis), a novel Janus kinase-1 and -2 inhibitor. This patient's wound had previously been refractory to multiple surgical interventions and immunosuppression. After the initiation of ruxolitinib, the patient underwent successful split-thickness skin grafting, with resultant healing of his wounds...
November 2013: Journal of Foot and Ankle Surgery: Official Publication of the American College of Foot and Ankle Surgeons
Emily W Lowery, Susan M Schneider
Myelofibrosis (MF) is a blood cancer characterized by fibrotic bone marrow and altered hematopoiesis. Although the prevalence of MF is low, its severe symptoms have a significantly negative impact on patient quality of life, and its ability to transform into leukemia increases morbidity. Conventional drug therapies provide modest symptom palliation, but allogeneic stem cell transplantation has been the only treatment capable of affecting MF's natural history. Ruxolitinib (Jakafi®) is a new targeted therapy indicated to treat patients with intermediate- and high-risk MF...
June 2013: Clinical Journal of Oncology Nursing
Clodagh Keohane, Ruben Mesa, Claire Harrison
In 2005, the description of the JAK2V617F mutation for the first time provided a molecular key to enable more rapid diagnosis and target for novel therapeutics in the myeloproliferative neoplasms. In 2007, the first-in-class agent INC18424, ruxolitinib, JAKafi, or JAKAVI was first tested in patients with intermediate-risk 2 or high-risk myelofibrosis regardless of whether they possessed the JAK2V617F mutation. Patients treated with this agent had major reduction in splenomegaly as well as impressive reduction, and in some cases resolution, of symptoms...
2013: American Society of Clinical Oncology Educational Book
Paul Collier, Keyur Patel, Paul Waeltz, Mark Rupar, Rajyalakshmi Luthra, Phillip C C Liu, Gregory Hollis, Reid Huber, Srdan Verstovsek, Timothy C Burn
The substitution of valine with phenylalanine at amino acid 617 of the Janus kinase 2 (JAK2) gene (JAK2 p.V617F) occurs in a high proportion of patients with myeloproliferative neoplasms (MPNs). The ability to accurately measure JAK2 p.V617F allele burden is of great interest given the diagnostic relevance of the mutation and the ongoing clinical evaluation of JAK inhibitors. A main hurdle in developing quantitative assays for allele burden measurement is the unavailability of accurate standards for both assay validation and use in a standard curve for quantification...
May 2013: Genetic Testing and Molecular Biomarkers
Brian W Dymock, Cheng Shang See
INTRODUCTION: Janus kinases (JAKs) comprise a family of four enzymes, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), centrally implicated in cell signaling processes important in cancer and immune-inflammatory diseases. Progression in the field has taken a recent step forward with the approval of ruxolitinib (Jakafi), a selective inhibitor of JAK1/2 and very recently tofacitinib (Xeljanz), a pan-JAK inhibitor. There are many new JAK family enzyme inhibitors in the clinic now with a range of selectivity profiles...
April 2013: Expert Opinion on Therapeutic Patents
H Malhotra
Janus Activated Kinase (JAK) 2 plays an important role in the pathogenesis of myelofibrosis (MF). Ruxolitinib (INCB018424, Jakafi) is a potent dual JAK1 and JAK2 inhibitor. In November 2011, it became approved by the US FDA for the treatment of intermediate or high-risk MF. This review shall outline the role of Ruxolitinib in the current management of MF and its potential future.
July 2012: Indian Journal of Cancer
Albert Deisseroth, Edvardas Kaminskas, Joseph Grillo, Wei Chen, Haleh Saber, Hong L Lu, Mark D Rothmann, Satjit Brar, Jian Wang, Christine Garnett, Julie Bullock, Laurie B Burke, Atiqur Rahman, Rajeshwari Sridhara, Ann Farrell, Richard Pazdur
On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.), an inhibitor of the Janus kinases 1 and 2, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (study 1) or best available therapy (study 2)...
June 15, 2012: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
John Mascarenhas, Ronald Hoffman
The BCR-ABL1-negative myeloproliferative neoplasms (e.g., essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains. Hematopoietic stem cell transplant offers the only potential for cure in a minority of eligible patients, leaving a serious unmet need for improved therapies...
June 1, 2012: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
(no author information available yet)
No abstract text is available yet for this article.
April 2, 2012: Medical Letter on Drugs and Therapeutics
Matthew M Seavey, Pawel Dobrzanski
Janus kinases have proved to be essential for many immunological processes but there is growing evidence that they also play a critical role in pathogenesis of many diseases including inflammatory diseases and cancer where they promote multiple steps of tumorigenesis. Several companies are in late stage clinical programs for the development of JAK kinase inhibitors and the first small molecule JAK inhibitor, Jakafi® (ruxolitinib) has been just approved for treatment of myeloproliferative neoplasms. Several other molecules are on the rise to treat arthritis, psoriasis and multiple types of cancer...
May 1, 2012: Biochemical Pharmacology
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