title: Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy.
abstract: Targeting the stromal cell-derived factor 1α (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell-derived factor 1 (SDF-1)α-induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1α/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and β-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1α/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea;
authors.forename: Byung-Sik
authors.initials: BS
authors.lastname: Cho
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.affiliation: Department of Lymphoma and Myeloma, and.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Teresa
authors.initials: T
authors.lastname: McQueen
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Marszalek
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Sheng-Bin
authors.initials: SB
authors.lastname: Peng
authors.affiliation: Department of Lymphoma and Myeloma, and.
authors.forename: Wencai
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Lymphoma and Myeloma, and.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Thornton
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000595455:LY2510924; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4