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

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

Fingerprint

CXC Chemokines
Chemotherapy
Chemokine Receptors
Combination Drug Therapy
Acute Myeloid Leukemia
Stromal Cells
Myeloid Cells
Chemokine CXCL12
Catenins
Cell death
Phosphatidylinositol 3-Kinases
Gene expression
Tumors
Gene Expression Profiling
Chemotaxis
Tumor Burden
Molecules
Cell Death
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Cho, B. S., Zeng, Z., Mu, H., Wang, Z., Konoplev, S., McQueen, T., ... 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

Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy. / Cho, Byung Sik; Zeng, Zhihong; Mu, Hong; Wang, Zhiqiang; Konoplev, Sergej; McQueen, Teresa; Protopopova, Marina; Cortes, Jorge; Marszalek, Joseph R.; Peng, Sheng Bin; Ma, Wencai; Davis, R. Eric; Thornton, Donald E.; Andreeff, Michael; Konopleva, Marina.

In: Blood, Vol. 126, No. 2, 09.07.2015, p. 222-232.

Research output: Contribution to journalArticle

Cho, BS, Zeng, Z, Mu, H, Wang, Z, Konoplev, S, McQueen, T, Protopopova, M, Cortes, J, Marszalek, JR, Peng, SB, Ma, W, Davis, RE, Thornton, DE, Andreeff, M & Konopleva, M 2015, 'Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy', Blood, vol. 126, no. 2, pp. 222-232. https://doi.org/10.1182/blood-2015-02-628677
Cho, Byung Sik ; Zeng, Zhihong ; Mu, Hong ; Wang, Zhiqiang ; Konoplev, Sergej ; McQueen, Teresa ; Protopopova, Marina ; Cortes, Jorge ; Marszalek, Joseph R. ; Peng, Sheng Bin ; Ma, Wencai ; Davis, R. Eric ; Thornton, Donald E. ; Andreeff, Michael ; Konopleva, Marina. / Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy. In: Blood. 2015 ; Vol. 126, No. 2. pp. 222-232.
@article{02c42428a2884a839bce83d4db69c59a,
title = "Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy",
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.",
author = "Cho, {Byung Sik} and Zhihong Zeng and Hong Mu and Zhiqiang Wang and Sergej Konoplev and Teresa McQueen and Marina Protopopova and Jorge Cortes and Marszalek, {Joseph R.} and Peng, {Sheng Bin} and Wencai Ma and Davis, {R. Eric} and Thornton, {Donald E.} and Michael Andreeff and Marina Konopleva",
year = "2015",
month = "7",
day = "9",
doi = "10.1182/blood-2015-02-628677",
language = "English (US)",
volume = "126",
pages = "222--232",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "2",

}

TY - JOUR

T1 - Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy

AU - Cho, Byung Sik

AU - Zeng, Zhihong

AU - Mu, Hong

AU - Wang, Zhiqiang

AU - Konoplev, Sergej

AU - McQueen, Teresa

AU - Protopopova, Marina

AU - Cortes, Jorge

AU - Marszalek, Joseph R.

AU - Peng, Sheng Bin

AU - Ma, Wencai

AU - Davis, R. Eric

AU - Thornton, Donald E.

AU - Andreeff, Michael

AU - Konopleva, Marina

PY - 2015/7/9

Y1 - 2015/7/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937840502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937840502&partnerID=8YFLogxK

U2 - 10.1182/blood-2015-02-628677

DO - 10.1182/blood-2015-02-628677

M3 - Article

C2 - 26031918

AN - SCOPUS:84937840502

VL - 126

SP - 222

EP - 232

JO - Blood

JF - Blood

SN - 0006-4971

IS - 2

ER -