TY - JOUR
T1 - CXCR4 protein epitope mimetic antagonist POL5551 disrupts metastasis and enhances chemotherapy effect in triple-negative breast cancer
AU - Xiang, Jingyu
AU - Hurchla, Michelle A.
AU - Fontana, Francesca
AU - Su, Xinming
AU - Amend, Sarah R.
AU - Esser, Alison K.
AU - Douglas, Garry J.
AU - Mudalagiriyappa, Chidananda
AU - Luker, Kathryn E.
AU - Pluard, Timothy
AU - Ademuyiwa, Foluso O.
AU - Romagnoli, Barbara
AU - Tuffin, Gérald
AU - Chevalier, Eric
AU - Luker, Gary D.
AU - Bauer, Michael
AU - Zimmermann, Johann
AU - Aft, Rebecca L.
AU - Dembowsky, Klaus
AU - Weilbaecher, Katherine N.
N1 - Funding Information:
The authors thank Michael Tomasson, John DiPersio, David DeNardo, Melissa Meyer, Yu Zhu, and Michael Ross for their valuable expert suggestions and criticism. The authors thank Yalin Xu, Lynne Collins, and Julie Prior for their technical assistance. The authors thank Dr. Mark Watson for the supervision of the gene array data generation. This research was supported by grants from NIH CA097250 (to K.N. Weilbaecher, M.A. Hurchla, J. Xiang, X. Su, and F. Fontana), NIH CA100730 (to K.N. Weilbaecher, J. Xiang, and A.K. Esser), NIH CA154737 (to K.N. Weilbaecher, A.K. Esser), NIH research fellowship 1F31CA174096-01A1 (to S.R Amend), NIH 1K12CA167540 (to F.O. Ademuyiwa), NIH R01CA172623 (to R.L. Aft and C. Mudalagiriyappa), NIH CA170198, CA142750, and CA182333 (to G.D. Luker and K.E Luker). Targeted funding to purchase NSG mice for a subset of experiments was provided by Polyphor Ltd. This study was also supported by the Musculoskeletal Research Center for microCT (NIH P30 AR057235), the P50 small animal imaging core for bioluminescence studies (CA94056), the DDRCC Morphology core (grant P30 DK52574), The Barnes- Jewish Foundation, The St. Louis Men''s Group against Cancer, and Hope Center Alafi Neuroimaging Laboratory (NIH Shared Instrumentation grant S10 RR027552). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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 triplenegative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distantmetastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival inmice 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, weused 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.
AB - 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 triplenegative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distantmetastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival inmice 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, weused 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.
UR - http://www.scopus.com/inward/record.url?scp=84958177064&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-15-0252
DO - 10.1158/1535-7163.MCT-15-0252
M3 - Article
C2 - 26269605
AN - SCOPUS:84958177064
SN - 1535-7163
VL - 14
SP - 2473
EP - 2485
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 11
ER -