JAK Inhibition: Blocking Cytokine Signaling in Cancer Cells

Lisa Raedler, PhD, RPh

Cells 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

What is the current clinical role of JAK inhibitors? Based on knowledge of JAK-STAT pathway alterations and JAK mutations, researchers have evaluated JAK inhibitors in the context of MPDs, leukemias, lymphomas, and other relevant cancers as well as autoimmune conditions such as rheumatoid arthritis (RA). The Table summarizes JAK inhibitors that are approved for use or in late-stage clinical development as of June 2013. There are 2 JAK inhibitors currently approved for use in the United States, tofacitinib and ruxolitinib. Because tofacitinib primarily inhibits JAK3 and JAK1, its clinical development focused on the agent’s immunomodulatory properties in the context of RA and other immune-mediated diseases.^13,14 Multiple phase 2 and phase 3 trials established the efficacy and safety of tofacitinib in RA,^15-19 and there are active trials of tofacitinib in inflammatory bowel disease and psoriasis (eg, NCT01465763, NCT01831466).²⁰ In 2012, phase 3 data were submitted to the US Food and Drug Administration (FDA) demonstrating the efficacy of tofacitinib monotherapy, as well as the combination of tofacitinib and methotrexate, in patients with RA who failed disease-modifying antirheumatic drugs.^17,21 In November 2012, tofacitinib was FDA approved for use in patients with moderately to severely active RA who have had an inadequate response to, or who are intolerant of, methotrexate.²² As of June 2013, 2 other JAK inhibitors—baricitinib and VX-509—are in latestage clinical development for RA and other autoimmune conditions.^23,24 In November 2011, ruxolitinib (Jakafi), which inhibits JAK1 and JAK2, was FDA approved for the treatment of patients with intermediate or high-risk MF, including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.²⁵ Ruxolitinib’s approval was based on results from 2 randomized phase 3 trials, known as COMFORT-I and COMFORT-II, that enrolled more than 500 patients in more than 150 study sites throughout the world.^20,26-29 These studies independently demonstrated that ruxolitinib was significantly superior to the comparator arm with regard to reduction of spleen size and MF symptom burden.^27,28 In both of these trials, ruxolitinib’s clinical benefits were observed regardless of patients’ JAK mutational status.^27,28 In December 2012, long-term follow-up data from COMFORT-I and COMFORT-II were presented at the American Society of Hematology meeting.^30,31 These data showed that patients receiving ruxolitinib had significantly improved overall survival compared with both placebo and best available therapy.²⁹ Longterm data from COMFORT-I also demonstrated an association between ruxolitinib treatment and durable improvements in quality of life, including the 5 functional domains of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Questionnaire (quality of life self-rating instrument).³⁰ In both pivotal phase 3 studies, ruxolitinib was associated with myelosuppression, including grade 3 or 4 thrombocytopenia and grade 3 or 4 anemia, as well as a need for red blood cell (RBC) transfusions during the study. These events were deemed manageable and rarely led to ruxolitinib discontinuation.^30,31 Of note, the long-term COMFORT-I study update presented in 2012 indicated that the proportion of patients on ruxolitinib receiving RBC transfusions decreased to the level seen among patients receiving placebo by week 36 of the study and remained stable thereafter. There were also no new reports of leukemic transformation, and no specific patterns of adverse events (AEs) or reports of a withdrawal syndrome after ruxolitinib discontinuation were observed with longer follow-up.³⁰ What are the next steps in JAK science and drug development? In addition to ruxolitinib for MF, 3 other JAK inhibitors are in clinical trials for MF and other tumor types: SAR302503 (TG101348), pacritinib (SB1518), and CYT387. SAR302503 SAR302503 is a selective JAK2 inhibitor in development for MF and solid tumors. In December 2012, Talpaz and colleagues reported data from a phase 2 study evaluating SAR302503 in 31 patients with MF randomized to doses of 300 mg, 400 mg, or 500 mg per day for 12 weeks. At the time of analysis, the median percentage reduction in spleen volume from baseline ranged from 30% to 42% in a dose-dependent fashion. MF-related symptoms were also reduced. The most common grade 3 or 4 nonhematologic AEs were gastrointestinal; none led to permanent drug discontinuation. Grade 3 or 4 hematologic toxicities were anemia and thrombocytopenia.³² In May 2013, the manufacturer of SAR302503 announced favorable results from the drug’s pivotal study, known as JAKARTA. This multinational, randomized, double-blind, placebo-controlled, phase 3 study enrolled 289 patients with intermediate-2 or high-risk primary MF, post–polycythemia vera MF, or post–essential thrombocythemia MF. Eligible patients had platelet counts of at least 50,000/μL. Patients received either once-daily oral SAR302503 (400 mg or 500 mg) or placebo for a total of 24 weeks. In both Pacritinib caused further minimal bone marrow suppression, regardless of patients’ initial platelet counts. Specifically, patients whose initial platelet counts were less than 50,000/µL tolerated pacritinib therapy, maintained stable blood and platelet counts, and did not require dose reductions for thrombocytopenia. Among the full patient cohort, grade 1 or 2 gastrointestinal events, particularly diarrhea, were the most common AEs. These events were effectively controlled with early administration of standard antidiarrheal agents.³⁵ PERSIST-1, a randomized controlled phase 3 trial comparing the efficacy of pacritinib with the efficacy of best available therapy (defined within the study as any physician-selected MF treatment, excluding JAK inhibitors) in patients with MF, is currently under way. In light of pacritinib’s relative lack of bone marrow suppression, there are no study enrollment restrictions due to thrombocytopenia or anemia. Patients with MF who are platelet- and RBC transfusion–dependent may enroll in the PERSIST-1 trial.³⁶ CYT387 CYT387 is an orally available small molecule inhibitor of JAK1 and JAK2. In December 2012, Pardanani and colleagues presented updated results from a phase 1/2 multicenter study in which CYT387 demonstrated rapid and sustained improvements in splenomegaly and constitutional symptoms as well as in transfusion requirements.³⁷ In this study, 166 subjects were enrolled and followed for a median of 16.1 months. Of interest, transfusion independence was observed in more than half of the RBC transfusion–dependent subjects in this study, with the maximum transfusion-free period exceeding 2 years. The proportion of all subjects who required RBC transfusions over the treatment period also decreased substantially. The most common treatment-related AEs associated with CYT387 included thrombocytopenia, peripheral neuropathy (sensory), dizziness, diarrhea, nausea, and headache.³⁷ A phase 3 trial of CYT387 in MF is expected to begin in the latter half of 2013.³⁸ In summary, the discovery of JAKs, JAK mutations, and the JAK-STAT pathway has clarified the pathophysiology of diseases ranging from primary immunodeficiencies to life-threatening cancers.³ For the oncology community, this new avenue of cell signaling research and subsequent exploration of JAK inhibitors offers exciting possibilities for improved outcomes in patients with cancer with limited treatment alternatives.

References

1. Kopf M, Bachmann MF, Marsland BJ. Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov. 2010;9:703-718.
2. Stark GR, Darnell JE. The JAK-STAT pathway at twenty. Immunity. 2012;36:503-514.
3. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency,and cancer. N Engl J Med. 2013;368:161-170.
4. 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.
5. Boulay JL, O’Shea JJ, Paul WE. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity. 2003;19:159-163.
6. Leonard WJ, O’Shea JJ. JAKs and STATs: biological implications. Ann Rev Immunol. 1998;16:293-322.
7. 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.
8. Chen E, Staudt LM, Green AR. Janus kinase deregulation in leukemia and lymphoma. Immunity. 2012;36:529-541.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. ClinicalTrials,gov Web site. http://clinicaltrials.gov/. Accessed July 9, 2013.
21. 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.
22. Press release, November 6, 2012. FDA approves Xeljanz for rheumatoid arthritis. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm. Accessed July 9, 2013.
23. 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.
24. Cohen S. Promise and pitfalls of kinase inhibitors for rheumatoid arthritis. Int J Clin Rheum. 2012;7:413-423.
25. 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.
26. Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2013.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. ClinicalTrials.gov Web site. Oral pacritinib versus best available therapy to treat myelofibrosis. http://clinicaltrials.gov/show/NCT01773187. Accessed July 9, 2013.
37. 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.
38. 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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