title: Decitabine priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia.
abstract: The prognosis of acute myeloid leukemia (AML) is poor, highlighting the need for novel treatments. Hypomethylating agents, including decitabine are used to treat elderly AML patients with relative success. Targeting nuclear export receptor (exportin 1 [XPO1]) is a novel approach to restore tumor suppressor (TS) function in AML. Here, we show that sequential treatment of AML blasts with decitabine followed by selinexor (XPO1 inhibitor) enhances the antileukemic effects of selinexor. These effects could be mediated by the re-expression of a subset of TSs (CDKN1A and FOXO3A) that are epigenetically silenced via DNA methylation, and cytoplasmic-nuclear trafficking is regulated by XPO1. We observed a significant upregulation of CDKN1A and FOXO3A in decitabine- versus control-treated cells. Sequential treatment of decitabine followed by selinexor in an MV4-11 xenograft model significantly improved survival compared with selinexor alone. On the basis of these preclinical results, a phase 1 clinical trial of decitabine followed by selinexor in elderly patients with AML has been initiated.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Parvathi
authors.initials: P
authors.lastname: Ranganathan
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hofstetter
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Alison
authors.initials: A
authors.lastname: Walker
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Walsh
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Bhatnagar
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klisovic
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Sumithira
authors.initials: S
authors.lastname: Vasu
authors.affiliation: The College of Pharmacy, The Ohio State University, Columbus, OH; and.
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Steven
authors.initials: S
authors.lastname: Devine
authors.affiliation: Karyopharm Therapeutics, Inc., Natick, MA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Karyopharm Therapeutics, Inc., Natick, MA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center, and.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D006834:Hydrazines / Q000627:therapeutic use*; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D001374:Azacitidine; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015254:DNA Modification Methylases; D000077209:Decitabine; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C499517:FOXO3 protein, human; C585161:selinexor