Methods and pharmaceutical compositions for the treatment of systemic mastocytosis

Abstract

The present invention relates to methods and pharmaceutical compositions for the treatment of systemic mastocytosis. The inventors showed the effect of KPT-251 treatment on SCF-dependent human Mast cell (MC) line without KIT mutation (WT ROSA) and on two factor-independent MC lines with KIT mutations: ROSA Δ 417-419 insY and ROSA D816V. KPT is a Selective Inhibitor of Nuclear Export (SINE) that specifically inhibits the activity of the exportin-1 (XPO1). KPT-251 treatment induces minimal toxicity in non-cancerous hematopoietic cells both in vitro and in vivo. In particular, the present invention relates a method of treating systemic mastocytosis in patient in need thereof comprising administering to the patient a therapeutically effective amount of a XPO1 inhibitor.

1 . A method of treating systemic mastocytosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a XPO1 inhibitor. 
     
     
         2 . The method of  claim 1  wherein the patient suffers from indolent SM (ISM), SM with associated clonal hematologic non-MC disease, aggressive SM (ASM), or MC leukemia (MCL). 
     
     
         3 . The method of  claim 1  wherein the patient harbors the KIT mutation D816V or Delta 417-419 insY. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1  wherein the XPO1 inhibitor is a short hairpin RNA (shRNA), a small interfering RNA (siRNA) or an antisense oligonucleotide which inhibits the expression of XPO1. 
     
     
         6 . The method of  claim 2  wherein the XPO1 inhibitor is KPT-330, KPT-276, or KPT-251. 
     
     
         7 . The method of  claim 3  wherein the XPO1 inhibitor is KPT-330, KPT-276, or KPT-251.