Mechanism of Action: Key Advances in Hematology Oncology
JAK Inhibition: Blocking Cytokine Signaling in Cancer CellsCells in living organisms function and grow in response to cell-signaling cytokines, including various proteins, peptides, and glycoproteins. Given their central role in the body’s regulation of cell growth and immune responses, cytokines are highly appealing targets for therapeutic intervention in various diseases, including inflammatory conditions, bone disorders, metabolic diseases, wound healing, and cancer.1 The year 2012 marked the 20th anniversary of the discovery of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway.2 Prompted by efforts to understand the biology of interferon (IFN), an immunomodulatory cytokine, research regarding the JAK-STAT pathway has resulted in the development of novel pharmacologic agents with clinical activity in rheumatoid arthritis and myelofibrosis (MF).3 What do JAKs do in normal cells? Various cytokines, including interleukins (ILs), IFNs, and colony stimulating factor, as well as classic hormones (eg, erythropoietin, prolactin, growth hormone), bind to specific cell surface receptors to affect cell functioning and growth.4 The signaling function via these receptors begins with JAKs, a family of 4 structurally distinct enzymes (kinases) with apparently restricted function: JAK1, JAK2, JAK3, and TYK2.5 After cytokines bind to specific cell surface receptors (known as type I and type II receptors), JAKs phosphorylate those receptors. This, in turn, results in the recruitment of various signaling intermediates, including STATs.5 Upon entering the cell’s nucleus, STATs induce the transcription of specific genes.6 These genes, known as IFN-stimulated genes, are involved in various cellular processes, including proliferation, differentiation, and cell death. Why target JAKs in cancer? The JAK-STAT pathway is understood to be highly relevant in the development and progression of cancer7:
- JAK mutations have been found in leukemias and myeloproliferative disorders (MPDs), such as MF.8 For example, patients with MPDs harbor a gain-of-function JAK2 mutation.9 These patients with cancer have been shown to have a significantly longer duration of disease as well as higher complication rates (eg, fibrosis, hemorrhage, and thrombosis) than patients with wild-type JAK2.9
- Alterations in the JAK-STAT pathway have been identified in a variety of solid tumors, including head and neck, breast, lung, and prostate cancer.10,11 In many of these solid tumor cells, as well as in diffuse large B-cell lymphoma, JAKs mediate IL-6 signaling, which has been implicated in tumorigenesis.8,10,11
- In several cancer cell types, JAKs are believed to promote chemoresistance in response to elevated levels of fibroblast growth factor-2.7,12
- Kopf M, Bachmann MF, Marsland BJ. Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov. 2010;9:703-718.
- Stark GR, Darnell JE. The JAK-STAT pathway at twenty. Immunity. 2012;36:503-514.
- O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency,and cancer. N Engl J Med. 2013;368:161-170.
- Kontzias A, Kotlyar A, Laurence A, et al. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol. 2012;12:464-470.
- Boulay JL, O’Shea JJ, Paul WE. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity. 2003;19:159-163.
- Leonard WJ, O’Shea JJ. JAKs and STATs: biological implications. Ann Rev Immunol. 1998;16:293-322.
- Costa-Pereira AP, Bonito NA, Seckl MJ. Dysregulation of janus kinases and signal transducers and activators of transcription in cancer. Am J Cancer Res. 2011;1:806-816.
- Chen E, Staudt LM, Green AR. Janus kinase deregulation in leukemia and lymphoma. Immunity. 2012;36:529-541.
- Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.
- Gao SP, Mark KG, Leslie K, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117:3846-3856.
- Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009;16:487-497.
- Carmo CR, Lyons-Lewis J, Seckl MJ, Costa-Pereira AP. A novel requirement for Janus kinases as mediators of drug resistance induced by fibroblast growth factor-2 in human cancer cells. PLoS One. 2011;6:e19861.
- Ghoreschi K, Jesson MI, LiX, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186:4234-4243.
- LaBranche TP, Jesson MI, Radi ZA, et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 2012;64:3531-3542.
- Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIB dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012;64:617-629.
- Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 2011;63:1150-1158.
- Wollenhaupt J, Silverfield JC, Lee EB, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: open-label, long-term extension studies up to 36 months. Arthritis Rheum. 2011;63(suppl 10). Abstract 407.
- Van Vollenhoven RF, Fleischmann RF, Cohen RM, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, or adalimumab versus placebo in patients with rheumatoid arthritis on background methotrexate: a phase 3 study. Arthritis Rheum. 2011;63(suppl 10). Abstract 408.
- Cohen S, Radominski SC, Asavatanabodee P, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor: analysis of infections and all-cause mortality across phase 3 and long-term extension studies in patients with rheumatoid arthritis. Arthritis Rheum. 2011;63(suppl 10). Abstract 409.
- ClinicalTrials,gov Web site. http://clinicaltrials.gov/. Accessed July 9, 2013.
- Kremer J, LiZ-G, Hall S, et al. Tofacitinib (CP-690,550), an oral JAK inhibitor, in combination with traditional DMARDs: phase 3 study in patients with active rheumatoid arthritis with inadequate response to DMARDs. Ann Rheum Dis. 2011;70(suppl 3). Abstract 170.
- Press release, November 6, 2012. FDA approves Xeljanz for rheumatoid arthritis. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm. Accessed July 9, 2013.
- Press release, June 13, 2013. Lilly and Incyte announce baricitinib efficacy and safety data from the open-label, long-term extension of the phase 2b JADA study in patients with rheumatoid arthritis. http://newsroom.lilly.com/releasedetail.cfm?releaseid=771109. Accessed July 9, 2013.
- Cohen S. Promise and pitfalls of kinase inhibitors for rheumatoid arthritis. Int J Clin Rheum. 2012;7:413-423.
- Press release, November 16, 2011. FDA approves first drug to treat a rare bone marrow disease. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280102.htm. Accessed July 9, 2013.
- Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2013.
- Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798.
- Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
- Verstovsek S, Mesa RA, Hoffman R, et al. Updates on ruxolitinib from ASCO and ASH 2012, including long-term survival data. December 15, 2012. http://www.ascopost.com/issues/december-15-2012/updates-on-ruxolitinib-from-ascoand-ash-2012,-including-long-term-survival-data.aspx. Accessed July 9, 2013.
- Verstovsek S, Mesa RA, Gotlib J, et al. Long-term outcome of ruxolitinib treatment in patients with myelofibrosis: durable reductions in spleen volume, improvements in quality of life, and overall survival advantage in COMFORT-I. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 800.
- Cervantes F, Kiladjian J-J, Niederwieser D, et al: Long-term safety, efficacy, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF). Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 801.
- Talpaz M, Jamieson C, Gabrail NY, et al. A phase II randomized dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 2837.
- Press release, May 17, 2013. Sanofi reports positive topline results from pivotal phase III JAKARTA study for JAK2 inhibitor in myelofibrosis. http://en.sanofi.com/Images/33051_20130517_jakarta_en.pdf. Accessed July 9, 2013.
- ClinicalTrials.gov Web site. Phase II, open label, single arm study of SAR302503 in myelofibrosis patients previously treated with ruxolitinib (JAKARTA2). http://clinicaltrials.gov/ct2/show/NCT01523171. Accessed July 9, 2013.
- Verstovsek S, Liang SY, Komrokji R, et al. Safety overview of phase 1-2 studies of pacritinib, a non-myelosuppressive JAK2/FLT3 inhibitor, in patients with hematological malignancies. Haematologica. 2013;98(suppl 1). Abstract P278.
- ClinicalTrials.gov Web site. Oral pacritinib versus best available therapy to treat myelofibrosis. http://clinicaltrials.gov/show/NCT01773187. Accessed July 9, 2013.
- Pardanani A, Gotlib J, Gupta V, et al. Phase I/II study of CYT387, a JAK1/JAK2 inhibitor for the treatment of myelofibrosis. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 178.
- Press release, December 12, 2012. Gilead Sciences to acquire YM BioSciences, adds selective JAK inhibitor to growing oncology and inflammation pipeline. http://investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle&id=1766528. Accessed July 9, 2013.
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Analysis of the phase 3 randomized clinical trial PERSEPHONE showed that 6 months of treatment with trastuzumab was noninferior to 12 months in terms of disease-free survival, whereas a shorter course of trastuzumab was associated with a 50% reduction in cardiotoxicity.
In the cell nucleus, DNA is maintained in a tightly coiled state around proteins called histones.1 During the process of DNA replication for cell division or during the synthesis of RNA and proteins, histone acetyltransferase adds acetyl groups onto the histones, enabling DNA to uncoil.1 By contrast, histone deacetylases (HDACs) [ Read More ]