New generation small-molecule inhibitors in myeloproliferative neoplasms

Passamonti, Francesco; Maffioli, Margherita; Caramazza, Domenica

doi:10.1097/moh.0b013e32834ff575

Cited by 25 publications

(9 citation statements)

References 55 publications

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“…Other molecular events may precede the acquisition of JAK2V617F mutation in these disorders. Novel selective JAK2 inhibitors are the active focus for further clinical investigations [60,61,88]. …”

Section: Discussionmentioning

confidence: 99%

“…Several strategies have been proposed to inhibit or modulate this pathway [58,59]. JAK inhibitors are among the first successful agents reaching clinical application [60,61]. …”

Section: Novel Inhibitors Of Jak-stat Pathwaymentioning

confidence: 99%

“…This molecule selectively inhibited the JAK2 V617F-STAT5 signaling at a concentration that was 41-fold lower than that needed for the wild type (WT) JAK2 signaling (IC50 = 55 nM for V617F vs. 2260 nM for WT ) [60]. A phase I/II trial recruited 19 patients with Ph negative MPN.…”

Section: Jak Inhibitorsmentioning

confidence: 99%

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Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Furqan

Mukhi

Lee³

et al. 2013

Biomark Res

154

123

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JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK–STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Several strategies have been proposed to inhibit or modulate this pathway [58,59]. JAK inhibitors are among the first successful agents reaching clinical application [60,61]. …”

Section: Novel Inhibitors Of Jak-stat Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Furqan

Mukhi

Lee³

et al. 2013

Biomark Res

154

123

View full text Add to dashboard Cite

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“…8,12 Targeting tyrosine kinases upstream from STAT3 by using small-molecule inhibitors of JAK, SRC, c-KIT, and FLT3 provided an alternative strategy for AML therapy, but therapeutic effects in most clinical trials were shortlived. 8,13 Growing evidence suggests that to generate long-lasting effects, cancer immunotherapies need to alleviate tumor tolerance before jump-starting antitumor immune responses. 2,14 We have previously shown that STAT3 activity in tumor-associated myeloid cells hampered the effect of locally administered CpGoligodeoxyribonucleotide (ODN), a Toll-like receptor 9 (TLR9) ligand and clinically relevant immunoadjuvant.…”

Section: Introductionmentioning

confidence: 99%

Leukemia cell–targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity

Hossain¹,

Santos

Zhang³

et al. 2014

Blood

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“…Conversely, survival of patients with secondary myelofibrosis (sMF) post-polycythemia vera 4 and essential thrombocythemia 5 is unknown. [6][7][8] Among JAK-inhibitors, [9][10][11] ruxolitinib was the only one approved for the treatment of MF (PMF and sMF). The 2 prospective, randomized, phase III studies with ruxolitinib, named COMFORT-1 (vs placebo) 12 and COMFORT-2 (vs best available therapy [BAT]), 13 included patients with intermediate-2 and high IPSS risk MF with circulating blast cells ,10%.…”

Section: Introductionmentioning

confidence: 99%

Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts

Passamonti

Maffioli

Cervantes

et al. 2014

Blood

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The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF

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New generation small-molecule inhibitors in myeloproliferative neoplasms

Abstract: Patients who might benefit from JAK2 inhibitors in clinical practice are mostly those with splenomegaly or with constitutional symptoms. We should alert patients with lower hemoglobin levels that these therapies might, although temporarily, favor the need for red blood cell transfusions.

Cited by 25 publications

References 55 publications

Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Leukemia cell–targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity

Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts

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