Abstract
Abstract Disruption of the SDF-1α/CXCR4 axis by CXCR4 inhibitors has been proven to be an attractive investigational therapeutic approach for acute myeloid leukemia (AML). Moreover, the addition of CXCR4 inhibitor plerixafor to cytotoxic chemotherapy in a phase 1/2 study was associated with increased response rates in relapsed AML (Blood 2012:119;3917). However, plerixafor as a single agent induces only 2- to 4-fold mobilization of leukemic blasts, and this is thought to be due to incomplete inhibition of the SDF-1α/CXCR4 axis and short half-life. LY2510924 is a selective peptidic CXCR4 antagonist that blocks SDF-1α from binding to the receptor. Flow cytometry using OCI-AML3 cells showed that LY2510924 inhibited binding of anti-CXCR4 antibody 12G5 to surface CXCR4 in a concentration-dependent fashion. LY2510924 was 100 times more potent compared to plerixafor (normalized surface expression, LY2510924 at 1 nM, 10.7±0.27%; plerixafor at 1 nM and 100 nM, 74.6±1.23% and 11.0±0.29%, respectively). The action of LY2510924 started as early as 1 minute and continued up to 72 hours at 10 nM. SDF-1α induced migration of OCI-AML3 and primary AML cells, which was abolished by 1 nM LY2510924 but not suppressed by 1 nM plerixafor. LY2510924 inhibited SDF-1α-induced AKT and/or ERK phosphorylation in AML cell lines (OCI-AML3 and U937) and primary AML cells as shown by immunoblotting and multi-parameter phospho-flow cytometry. To test the efficacy of LY2510924 in vivo, we injected OCI-AML3/luc/mCherry cells into sub-lethally irradiated NSG mice. Twelve days after cell injection, mice were randomized into 4 groups: control, cytarabine, LY2510924, and LY2510924 plus cytarabine. On day 21 after cell injection, we observed a 3.4±1.4-fold increase of circulating leukemic cells at 3 hours and a 24.1±15.4-fold mobilization at 24 hours after LY2510924 injection. Bioluminescence imaging demonstrated that mice treated with LY2510924 had lower leukemia burden than cytarabine-treated and control mice. On day 39, the combination group showed less luciferase activity than the LY2510924 group (P=0.034). Hematoxylin-eosin and immunohistochemical staining with human CD45 antibody demonstrated that the LY2510924-treated groups had a significant decrease in leukemic infiltration of bone marrow, spleen, liver, and lung. This anti-leukemia effect translated into a significant prolongation of survival in LY2510924-treated mice (40 days vs. 26 days, P<0.001). In summary, in vitro data showed that a novel peptidic CXCR4 antagonist, LY2510924, could effectively disrupt the SDF-1α/CXCR4 axis in AML cells and was more potent than plerixafor. In vivo data showed anti-leukemia effects of LY2510924 as a single agent. LY2510924's stronger potency than plerixafor, rapidity of action, and prolonged CXCR4-inhibitory effects will likely translate into a higher anti-leukemia potency than that of plerixafor in future clinical applications. Citation Format: Byung Sik Cho, Zhihong Zeng, Hong Mu, Teresa McQueen, Marina Protopopova, Jorge Cortes, Joe Marszalek, Sheng-Bin Peng, Donald E. Thornton, Michael Andreeff, Marina Konopleva. Novel peptidic CXCR4 antagonist LY2510924 disrupts the SDF-1α/CXCR4 axis resulting in anti-AML efficacy in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4768. doi:10.1158/1538-7445.AM2014-4768
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call