Cancer Therapy: Preclinical Combined Inhibition of Janus Kinase 1/2 for the Treatment of JAK2V617F-Driven Neoplasms: Selective Effects on Mutant Cells and Improvements in Measures of Disease Severity

Purpose: Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for the Philadelphia chromosome–negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy. Experimental Design: A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight, and disease-associated inflammatory markers were measured. Results: INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F mutation by blocking JAK-STAT signaling and inducing apoptosis. In vivo, INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon treatment. Conclusions: These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients with myeloproliferative diseases and other neoplasms associated with JAK dysregulation. (Clin Cancer Res 2009;15(22):6891–900) The myeloproliferative diseases (MPD) are clonal proliferative disorders of hematopoietic progenitor cells with unique pathobiologies. Their clinical presentations include an increase in circulating functional, differentiated myeloid cell lineages that largely define the particular MPD. Broadly, the MPDs can be categorized into those that that are Philadelphia chromosome negative or positive, the latter of which defines nearly all cases of chronic myeloid leukemia (CML; refs. 1, 2). The seminal discovery that the Philadelphia chromosome resulted from a 9;22 translocation and produces the BCR-ABL fusion oncoprotein defined the first MPD-associated mutant allele (reviewed in ref. 3). Authors' Affiliations: Departments of Applied Technology, Preclinical Biology, In vitro Biology, and Medicinal Chemistry, Incyte Corporation, Wilmington, Delaware Received5/21/09; revised7/27/09; accepted8/5/09;publishedOnlineFirst 11/3/09. The costs of publication of this article were defrayed in part by the payment of page charges. This articlemust therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints: Jordan S. Fridman, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE 19880. Phone: 302-498-6930; Fax: 1-302425-2768; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1298 6891 Clin Cancer Res 2009;15(22) November 15, 2009 www.aacrjournals.org Research. on July 20, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 3, 2009; DOI: 10.1158/1078-0432.CCR-09-1298