Emerging targeted therapies in myelofibrosis.
Conventional drugs for myelofibrosis are driven by clinical needs, primarily anemia and splenomegaly. With these therapies, stem cell transplantation remains the only potentially curative approach. The discovery that mutations affecting JAK2 or MPL lead to activation of the intracellular JAK-STAT signaling pathway, and that other mutations (TET2, EZH2, ASXL1, IDH1 and IDH2) interfere with the normal machinery of epigenetics, has prompted to the development of therapies targeted at controling the major disease mechanisms. JAK2 ATP competitive inhibitors (ruxolitinib, lestaurtinib, SAR302503, SB1518 and CYT387) or drugs that indirectly inhibit the JAK-STAT pathway (everolimus) have documented major effects on splenomegaly and its constitutional symptoms. Epigenetic drugs (demethylating agents and histone deacetylase inhibitors) have displayed only minor effects on the disease symptoms. Relenting disease progression remains an unmet clinical need.
Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Viale Golgi 19, 27100 Pavia, Italy. barosig@smatteo.pv.it
Giovanni
G
Barosi
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation / Q000187:drug effects; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D053614:Janus Kinase 2; D053612:Janus Kinases; D058570:TOR Serine-Threonine Kinases