How many JAK inhibitors in myelofibrosis?

Ferreira, Bruna Velosa; Harrison, Claire

doi:10.1016/j.beha.2014.07.010

Cited by 5 publications

(2 citation statements)

References 60 publications

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“…Even for drugs thought to selectively target a certain oncogenic protein, such as Bcr-Abl or janus kinase 2 (Jak2), many “off-target” molecules are being found, as scientists dig deeper into their mechanisms of action. In particular, Jak2 inhibitors are effective, even in patients not harboring these mutations (Cervantes, 2014 ; de Lavallade et al, 2013 ; Ferreira & Harrison, 2014 ; Rosenthal & Mesa, 2014 ). Furthermore, various mechanisms of acquired resistance to these small molecule inhibitors have led to the return of a broader approach.…”

Section: Introductionmentioning

confidence: 99%

Digging deep into “dirty” drugs – modulation of the methylation machinery

Pleyer

Greil

2015

Drug Metabolism Reviews

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DNA methylation and histone modification are epigenetic mechanisms that result in altered gene expression and cellular phenotype. The exact role of methylation in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remains unclear. However, aberrations (e.g. loss-/gain-of-function or up-/down-regulation) in components of epigenetic transcriptional regulation in general, and of the methylation machinery in particular, have been implicated in the pathogenesis of these diseases. In addition, many of these components have been identified as therapeutic targets for patients with MDS/AML, and are also being assessed as potential biomarkers of response or resistance to hypomethylating agents (HMAs). The HMAs 5-azacitidine (AZA) and 2′-deoxy-5-azacitidine (decitabine, DAC) inhibit DNA methylation and have shown significant clinical benefits in patients with myeloid malignancies. Despite being viewed as mechanistically similar drugs, AZA and DAC have differing mechanisms of action. DAC is incorporated 100% into DNA, whereas AZA is incorporated into RNA (80–90%) as well as DNA (10–20%). As such, both drugs inhibit DNA methyltransferases (DNMTs; dependently or independently of DNA replication) resulting in the re-expression of tumor-suppressor genes; however, AZA also has an impact on mRNA and protein metabolism via its inhibition of ribonucleotide reductase, resulting in apoptosis. Herein, we first give an overview of transcriptional regulation, including DNA methylation, post-translational histone-tail modifications, the role of micro-RNA and long-range epigenetic gene silencing. We place special emphasis on epigenetic transcriptional regulation and discuss the implication of various components in the pathogenesis of MDS/AML, their potential as therapeutic targets, and their therapeutic modulation by HMAs and other substances (if known). The main focus of this review is laid on dissecting the rapidly evolving knowledge of AZA and DAC with a special focus on their differing mechanisms of action, and the effect of HMAs on transcriptional regulation.

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Section: Introductionmentioning

confidence: 99%

Digging deep into “dirty” drugs – modulation of the methylation machinery

Pleyer

Greil

2015

Drug Metabolism Reviews

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“…The study discontinuation rate was lower at 300 mg QD than at 250 mg BID or 300 mg BID, with 2 cases of treatment cessation owing to nervous system disorders in the latter cohort. Three agents in this drug class (fedratinib, XL109 and AZD1480) have been discontinued owing to neurological events 30 and a persistent treatment-emergent peripheral neuropathy with momelotinib has been recently reported. 31 Although possible mechanisms underlying the neurotoxicity of fedratinib have been proposed, 32 , 33 there are currently insufficient data from which to generate a hypothesis surrounding neurologic events with NS-018.…”

Section: Discussionmentioning

confidence: 99%

A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis

et al. 2016

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NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK–signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1–2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion.

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Myeloproliferative Neoplasms

Reuther

2016

Progress in Molecular Biology and Translational Science

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How many JAK inhibitors in myelofibrosis?

Cited by 5 publications

References 60 publications

Digging deep into “dirty” drugs – modulation of the methylation machinery

Digging deep into “dirty” drugs – modulation of the methylation machinery

A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis

Myeloproliferative Neoplasms

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