A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer

Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC cont...

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Published in:	Breast cancer research : BCR 2020-01, Vol.22 (1), p.4-9, Article 4
Main Authors:	Goldstein, Lori J, Perez, Raymond P, Yardley, Denise, Han, Linda K, Reuben, James M, Gao, Hui, McCanna, Susan, Butler, Beth, Ruffini, Pier Adelchi, Liu, Yi, Rosato, Roberto R, Chang, Jenny C
Format:	Article
Language:	eng
Subjects:	Adult Aged Allosteric properties Animals Autophagy Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - pathology Breast Neoplasms - surgery Cancer metastasis Cancer stem cells Cancer therapies CD44 antigen Cloning CXCR1 Disease resistance Diseases Drug therapy ErbB-2 protein Female Flow cytometry Fluorescent antibody technique Gene expression Health aspects Humans Immunofluorescence Immunoglobulins Immunohistochemistry Laboratories Localization Medical research Metastases Metastasis Mice Middle Aged Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - pathology Patient Safety Patients Receptor, ErbB-2 - metabolism Receptors, Interleukin-8A - antagonists & inhibitors Receptors, Interleukin-8B - antagonists & inhibitors Recurrence (Disease) Reparixin Stem cell transplantation Stem cells Studies Sulfonamides - pharmacokinetics Sulfonamides - therapeutic use Surgery Tissue Distribution Tumors Xenografts
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Summary:	Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH or CD24 /CD44 CSC by flow cytometry, with consistent reduction by immunohistochemistry. Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH and CD24 /CD44 measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.
ISSN:	1465-542X 1465-5411 1465-542X