Blood Journal
Leading the way in experimental and clinical research in hematology

Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

  1. Parvathi Ranganathan1,*,
  2. Xueyan Yu1,*,
  3. Caroline Na1,
  4. Ramasamy Santhanam2,
  5. Sharon Shacham3,
  6. Michael Kauffman3,
  7. Alison Walker1,
  8. Rebecca Klisovic1,
  9. William Blum1,
  10. Michael Caligiuri1,
  11. Carlo M. Croce2,
  12. Guido Marcucci1,2, and
  13. Ramiro Garzon1
  1. 1Division of Hematology, Department of Medicine and
  2. 2Department of Molecular Virology, Immunology and Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; and
  3. 3Karyopharm Therapeutics, Boston, MA

Abstract

Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (eg, p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD–positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.

  • Submitted April 16, 2012.
  • Accepted June 1, 2012.
View Full Text