Abstract 4445: Selective inhibitor of nuclear exporter CRM1/XPO1, Selinexor (KPT-330), exhibits remarkable activity against AML leukemia-initiating cells while sparing normal hematopoietic cells
Authors: Etchin Julia , Le Bonnie Thi , Berezovskaya Alla , Conway Amy S. , Chen Weihsu C. , Kentsis Alex , Mansour Marc R. , Stone Richard M. , Galinsky Ilene A. , DeAngelo Daniel J. , McCauley Dilara , Kauffman Michael , Shacham Sharon , Wang Jean CY , Kung Andrew L. , Look Thomas 
Published: August 2015

Abstract
Current treatments for acute myeloid leukemia (AML) often fail to induce long-term remissions and are toxic to normal tissues, prompting the need to develop new targeted therapies. The frequent disease relapse that is observed in patients with AML is thought to occur because of the inability of the existing drugs to target the self-renewing leukemia-initiating cells (LICs). An attractive new strategy for AML therapy is inhibition of the nuclear export protein exporter 1 (XPO1), or CRM1. XPO1 regulates export of proteins that contain leucine-rich nuclear export signals (NES), including protein adaptors that mediate transport of RNA. XPO1 cargo encompass tumor suppressor proteins, cell cycle regulators, and apoptotic proteins. Recently, small molecule inhibitors of nuclear export (SINE) that inhibit the export function of XPO1 by targeting Cys528 in its NES-binding groove, were developed using an in silico molecular modeling. Selinexor (KPT-330), the orally bioavailable SINE compound, is in Phase 1 and 2 studies in adult patients with AML (NCT01607892 and NCT02088541) and in a Phase 1 study for relapsed childhood ALL and AML initiated in March 2014 (NCT02091245).
To define the anti-leukemic activity of selinexor against primary AML blasts and LICs in a clinically relevant setting, we established mouse models of primary human leukemia, or patient-derived xenografts (PDX), in which leukemic blasts from AML patients were transplanted into immunodeficient NOD-SCID-IL2Rcγnull (NSG) mice. Mice engrafted with leukemic blasts were treated with either vehicle or selinexor. Selinexor was highly active against blast cells from two of the three patients with poor-prognosis disease (cytogenetically normal AML with FLT3-ITD (AML-CN) and complex karyotype AML (AML-CK1 and AML-CK2)), as evidenced by a reduction in leukemic engraftment in primary mice after 4 weeks of treatment. Secondary transplantation assays indicated that selinexor greatly reduced the frequency of LICs in PDX models derived from all three patients (6- to 430- fold reduction compared to controls), indicating that this agent not only targets the bulk leukemic cells, but also eliminates LICs. These findings show that selinexor has potent activity against LICs, even when it has only moderate activity against the bulk AML cell population. Furthermore, preliminary results of combination studies of selinexor with Ara-C, a standard chemotherapeutic agent, demonstrate synergistic effect of the two drugs against LICs in a PDX model of AML-CN. Importantly, 4 weeks of selinexor treatment demonstrated minimal toxicity in mice engrafted with normal human CD34+ hematopoietic cells. These findings demonstrate that inhibition of nuclear export with selinexor overcomes an important obstacle to cure of AML, which is to destroy the very critical LIC compartment while sparing normal hematopoietic cells.
Citation Format: Julia Etchin, Bonnie Thi Le, Alla Berezovskaya, Amy S. Conway, Weihsu C. Chen, Alex Kentsis, Marc R. Mansour, Richard M. Stone, Ilene A. Galinsky, Daniel J. DeAngelo, Dilara McCauley, Michael Kauffman, Sharon Shacham, Jean CY Wang, Andrew L. Kung, Thomas Look. Selective inhibitor of nuclear exporter CRM1/XPO1, Selinexor (KPT-330), exhibits remarkable activity against AML leukemia-initiating cells while sparing normal hematopoietic cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4445. doi:10.1158/1538-7445.AM2015-4445