title: KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells.
abstract: Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing myeloid cells that have acquired aberrant survival, uncontrolled proliferation and a block in normal hematopoietic cell differentiation. Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which is inhibited by the drug selinexor, is an attractive new therapeutic target in AML. Selinexor has shown impressive activity in Phase I/II clinical trials for AML. Here we report the anti-leukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the central nervous system mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two or three times weekly regimen of selinexor, and exhibits greater anti-leukemic efficacy against both leukemic blasts and LICs in AML patient-derived xenograft models. Importantly, normal hematopoietic stem and progenitor cell (HSPC) frequency is not significantly reduced by KPT-8602, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. These findings strongly endorse clinical testing of KPT-8602 in patients with relapsed and refractory AML.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Etchin
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Berezovskaya
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Conway
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Galinsky
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Karyopharm Therapeutics, Newton, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Karyopharm Therapeutics, Newton, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Karyopharm Therapeutics, Newton, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics, Newton, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Karyopharm Therapeutics, Newton, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: J C Y
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001752:Blast Crisis / Q000188:drug therapy / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D006834:Hydrazines; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D014230:Triazoles; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C585161:selinexor