Ju W, Zhang M, Jiang JK et al.CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP. Blood 117:1938-1946

Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892-1374, USA.
Blood (Impact Factor: 10.45). 02/2011; 117(6):1938-46. DOI: 10.1182/blood-2010-09-305425
Source: PubMed

ABSTRACT The retrovirus, human T-cell-lymphotrophic virus-1 (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-I-encoded protein tax constitutively activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems that in turn activate the Jak3 (Janus kinase 3)/STAT5 (signal transducers and activators of transcription 5) pathway, suggesting a therapeutic strategy that involves targeting Jak3. We evaluated the action of the Jak3 inhibitor CP-690,550 on cytokine dependent ex vivo proliferation that is characteristic of peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL, or from those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15, and their receptors. CP-690,550 at 50 nM inhibited the 6-day ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by 67.1% and 86.4%, respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL T cells ex vivo. Finally, in an in vivo test of biological activity, CP-690,550 treatment of mice with a CD8 T-cell IL-15-transgenic leukemia that manifests an autocrine IL-15/IL-15Rα pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select patients with HTLV-I-associated ATL and HAM/TSP.

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Available from: John E Janik, Aug 24, 2015
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    • "Its clinical efficacy in RA was established in a 6-week phase 2A study where objective and subjective clinical endpoints were achieved (10, 11). It inhibits the function of lymphocytes and their inflammatory cytokines by inhibiting signal transduction pathways of JAKs (12). Representative cytokines inhibited include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 whose receptors have JAK3-mediated common γ chain (12). "
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    ABSTRACT: Tofacitinib, a novel Janus kinase inhibitor, may prevent structural damage in rheumatoid arthritis (RA). In this cohort study, we compared radiographic progression of hand joints between 21 RA patients who took tofacitinb for 18 months in a phase IIb and its extension study and 42 patients who took conventional disease modifying antirheumatic drugs (DMARDs), using simple erosion narrowing score. For tofacitinib group, changes before and after the treatment were also compared. The changes of erosion and sum scores were significantly less in tofacitinib than DMARDs group (for erosion, -0.60 ± 1.83 vs 0.51 ± 1.77, P = 0.038; for sum, -0.50 ± 1.72 vs 1.57 ± 4.13, P = 0.012). Joint space narrowing score (JSN) was also less in tofacitinib group (0.095 ± 0.58 vs 1.06 ± 2.60, P = 0.055). In tofacitinib group, yearly rates of both erosion and JSN were significantly decreased after administration of tofacitinib (For erosion, 0.62 ± 0.93 to -0.14 ± 0.48, P = 0.009; for JSN, 0.47 ± 0.64 to 0.03 ± 0.40, P = 0.032), as was change of sum score (1.09 ± 1.27 to -0.10 ± 0.63, P < 0.001). In conclusion, tofacitinib may prevent structural damage caused by RA.
    Journal of Korean medical science 08/2013; 28(8):1134-8. DOI:10.3346/jkms.2013.28.8.1134 · 1.27 Impact Factor
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    • "Promising clinical trial data have been observed for Tasocitinib (CP690, 550) [52] and VX-509 [53]. In addition, Tasocitinib was also shown to be effective in inhibition of JAK3 and STAT5 activation in peripheral blood mononuclear cells isolated from T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis [54]. The possibility of inhibitor resistance to these agents must not be overlooked. "
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    ABSTRACT: The non-receptor tyrosine kinase JAK2 is implicated in a group of myeloproliferative neoplasms including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2-selective inhibitors are currently being evaluated in clinical trials. Data from drug-resistant chronic myeloid leukemia patients demonstrate that treatment with a small-molecule inhibitor generates resistance via mutation or amplification of BCR-ABL. We hypothesize that treatment with small molecule inhibitors of JAK2 will similarly generate inhibitor-resistant mutants in JAK2. In order to identify inhibitor-resistant JAK2 mutations a priori, we utilized TEL-JAK2 to conduct an in vitro random mutagenesis screen for JAK2 alleles resistant to JAK Inhibitor-I. Isolated mutations were evaluated for their ability to sustain cellular growth, stimulate downstream signaling pathways, and phosphorylate a novel JAK2 substrate in the presence of inhibitor. Mutations were found exclusively in the kinase domain of JAK2. The panel of mutations conferred resistance to high concentrations of inhibitor accompanied by sustained activation of the Stat5, Erk1/2, and Akt pathways. Using a JAK2 substrate, enhanced catalytic activity of the mutant JAK2 kinase was observed in inhibitor concentrations 200-fold higher than is inhibitory to the wild-type protein. When testing the panel of mutations in the context of the Jak2 V617F allele, we observed that a subset of mutations conferred resistance to inhibitor, validating the use of TEL-JAK2 in the initial screen. These results demonstrate that small-molecule inhibitors select for JAK2 inhibitor-resistant alleles, and the design of next-generation JAK2 inhibitors should consider the location of mutations arising in inhibitor-resistant screens.
    PLoS ONE 08/2012; 7(8):e43437. DOI:10.1371/journal.pone.0043437 · 3.23 Impact Factor
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    • "It is interesting to note that Tasocitinib (CP-690,550) inhibits proliferation of peripheral blood mononuclear cells (PBMCs) from patients with chronic and smoldering form of ATLL or with HAM/TSP that manifest constitutive Jak3/STAT5 activation. This agent prolongs the survival of transgenic mice bearing human CD8 T-cell leukemia with IL-15/IL-15R autocrine growth loop required for leukemia cell survival (Ju 2011). These results suggest clinical effect of CP-690,550 on chronic and smoldering ATLL. "
    T-Cell Leukemia, 10/2011; , ISBN: 978-953-307-400-9
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