POL5551, a novel and potent CXCR4 antagonist, enhances sensitivity to chemotherapy in pediatric ALL

Edward Allan R. Sison, Daniel Magoon, Li Li, Colleen E. Annesley, Barbara Romagnoli, Garry J. Douglas, Gerald Tuffin, Johann Zimmermann, Patrick Brown

Research output: Contribution to journalArticle

Abstract

The importance of the cell surface receptor CXCR4 and the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is well-established in normal and malignant hematopoiesis. The Protein Epitope Mimetic POL5551 is a novel and potent antagonist of CXCR4. POL5551 efficiently mobilizes hematopoietic stem and progenitor cells, but its effects in acute lymphoblastic leukemia (ALL) have not been reported. Here, we demonstrate that POL5551 is a potent antagonist of CXCR4 in pre-B and T cell ALL cell lines and pediatric ALL primary samples. POL5551 has activity at nanomolar concentrations in decreasing CXCR4 antibody binding, blocking SDF-1'-mediated phosphorylation of ERK1/2, inhibiting SDF-1'-induced chemotaxis, and reversing stromal-mediated protection from chemotherapy. POL5551 is significantly more effective at inhibiting CXCR4 antibody binding than the FDA-approved CXCR4 inhibitor plerixafor in ALL cell lines and primary samples. We also show that treatment with POL5551 in vitro and cytarabine +/- POL5551 in vivo modulates surface expression of adhesion molecules, findings that may guide the optimal clinical use of POL5551. Finally, we demonstrate that POL5551 increases sensitivity to cytarabine in a xenograft model of a high-risk pediatric ALL, infant MLL-rearranged (MLL-R) ALL. Therefore, disruption of the CXCR4/SDF-1 axis with POL5551 may improve outcomes in children with high-risk ALL.

Original languageEnglish (US)
Pages (from-to)30902-30918
Number of pages17
JournalOncotarget
Volume6
Issue number31
DOIs
StatePublished - Jan 1 2015

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Keywords

  • Acute lymphoblastic leukemia
  • CXCR4
  • Chemokines
  • Microenvironment
  • Pediatric

ASJC Scopus subject areas

  • Oncology

Cite this

Sison, E. A. R., Magoon, D., Li, L., Annesley, C. E., Romagnoli, B., Douglas, G. J., Tuffin, G., Zimmermann, J., & Brown, P. (2015). POL5551, a novel and potent CXCR4 antagonist, enhances sensitivity to chemotherapy in pediatric ALL. Oncotarget, 6(31), 30902-30918. https://doi.org/10.18632/oncotarget.5094