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      The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies

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          Abstract

          Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.

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          Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.

          Srdan Verstovsek, Hagop Kantarjian, Ruben Mesa … (2010)
          Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)
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            Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors.

            Kodappully Siveen, Sakshi Sikka, Rohit Surana … (2014)
            Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling that is usually generated at cell surface receptors and thereby transmit it to the nucleus. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers). There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation results in the induction of apoptosis in tumor cells, and accordingly its pharmacological modulation by tyrosine kinase inhibitors, antisense oligonucleotides, decoy nucleotides, dominant negative proteins, RNA interference and chemopreventive agents have been employed to suppress the proliferation of various human cancer cells in culture and tumorigenicity in vivo. However, the identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade. Copyright © 2013 Elsevier B.V. All rights reserved.
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              Non-Hodgkin lymphoma.

              Kate Shankland, James Armitage, Barry W Hancock (2012)
              Lymphomas are solid tumours of the immune system. Hodgkin's lymphoma accounts for about 10% of all lymphomas, and the remaining 90% are referred to as non-Hodgkin lymphoma. Non-Hodgkin lymphomas have a wide range of histological appearances and clinical features at presentation, which can make diagnosis difficult. Lymphomas are not rare, and most physicians, irrespective of their specialty, will probably have come across a patient with lymphoma. Timely diagnosis is important because effective, and often curative, therapies are available for many subtypes. In this Seminar we discuss advances in the understanding of the biology of these malignancies and new, available treatments. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 13 September 2018
                Publication date Collection: September 2018
                Volume: 10
                Issue: 9
                Electronic Location Identifier: 327
                Affiliations
                [1 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; arora.loukik@ 123456u.nus.edu (L.A.); csiapk@ 123456nus.edu.sg (A.P.K.)
                [2 ]Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore 117599, Singapore; mdccwj@ 123456nus.edu.sg
                [3 ]Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
                [4 ]Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia
                [5 ]National University Cancer Institute, National University Health System, Singapore 119074, Singapore
                [6 ]Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; frank.arfuso@ 123456curtin.edu.au
                [7 ]Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore 119074, Singapore
                [8 ]School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6009, Australia
                Author notes
                [* ]Correspondence: phcgs@ 123456nus.edu.sg ; Tel.: +65-6516-3267
                Author information
                https://orcid.org/0000-0002-3754-5712
                Article
                Publisher ID: cancers-10-00327
                DOI: 10.3390/cancers10090327
                PMC ID: 6162647
                PubMed ID: 30217007
                SO-VID: 1e8b9898-768a-4bc2-be8d-10280b1c7965
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 12 July 2018
                Date accepted : 11 September 2018
                Categories
                Subject: Review

                Keywords: stat3,hematological malignancies,targeted inhibition,proliferation,anti-apoptosis
                Data availability:
                Keywords: stat3, hematological malignancies, targeted inhibition, proliferation, anti-apoptosis

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