Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy

Byung Sik Cho, Zhihong Zeng, Hong Mu, Zhiqiang Wang, Sergej Konoplev, Teresa McQueen, Marina Protopopova, Jorge Cortes, Joseph R. Marszalek, Sheng Bin Peng, Wencai Ma, R. Eric Davis, Donald E. Thornton, Michael Andreeff, Marina Konopleva

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Targeting the stromal cell derived factor 1a (SDF-1a)/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. LY2510924rapidly anddurably blocked surfaceCXCR4andinhibited stromal cell derived factor 1 (SDF-1)a 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-1a/CXCR4signaling andsuggestedreduced proliferationand induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and b-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1a/ CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications.

Original languageEnglish (US)
Pages (from-to)222-232
Number of pages11
JournalBlood
Volume126
Issue number2
DOIs
StatePublished - Jul 9 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Cho, B. S., Zeng, Z., Mu, H., Wang, Z., Konoplev, S., McQueen, T., Protopopova, M., Cortes, J., Marszalek, J. R., Peng, S. B., Ma, W., Davis, R. E., Thornton, D. E., Andreeff, M., & Konopleva, M. (2015). Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy. Blood, 126(2), 222-232. https://doi.org/10.1182/blood-2015-02-628677