CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer.
The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a "chemotherapy framing" dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases.
Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Jingyu
J
Xiang
Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Michelle A
MA
Hurchla
Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri.
Francesca
F
Fontana
Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Xinming
X
Su
Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Sarah R
SR
Amend
Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Alison K
AK
Esser
Polyphor Ltd., Allschwil, Switzerland.
Garry J
GJ
Douglas
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
Chidananda
C
Mudalagiriyappa
Department of Radiology, Center for Molecular Imaging, University of Michigan Medical School, Ann Arbor, Michigan. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, Michigan.
Kathryn E
KE
Luker
Saint Luke's Cancer Institute, Kansas City, Missouri.
Timothy
T
Pluard
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Foluso O
FO
Ademuyiwa
Polyphor Ltd., Allschwil, Switzerland.
Barbara
B
Romagnoli
Polyphor Ltd., Allschwil, Switzerland.
Gérald
G
Tuffin
Polyphor Ltd., Allschwil, Switzerland.
Eric
E
Chevalier
Department of Radiology, Center for Molecular Imaging, University of Michigan Medical School, Ann Arbor, Michigan. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, Michigan.
Gary D
GD
Luker
Polyphor Ltd., Allschwil, Switzerland.
Michael
M
Bauer
Polyphor Ltd., Allschwil, Switzerland.
Johann
J
Zimmermann
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
Rebecca L
RL
Aft
Polyphor Ltd., Allschwil, Switzerland.
Klaus
K
Dembowsky
Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. kweilbae@dom.wustl.edu.
Katherine N
KN
Weilbaecher
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
D054377:Chemokine CXCL12; D000939:Epitopes; D005663:Furans; D007659:Ketones; D011506:Proteins; D019718:Receptors, CXCR4; C515255:CXCL12 protein, human; C572528:POL5551; C490954:eribulin; D000095662:Polyether Polyketides