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

Lori J Goldstein, Raymond P Perez, Denise Yardley, Linda K Han, James M Reuben, Hui Gao, Susan McCanna, Beth Butler, Pier Adelchi Ruffini, Yi Liu, Roberto R Rosato, Jenny C Chang, Lori J Goldstein, Raymond P Perez, Denise Yardley, Linda K Han, James M Reuben, Hui Gao, Susan McCanna, Beth Butler, Pier Adelchi Ruffini, Yi Liu, Roberto R Rosato, Jenny C Chang

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC.

Clinical trial registration: Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.

Keywords: Autophagy; CXCR1; Cancer stem cells; Reparixin.

Conflict of interest statement

PAR, SMC, and BB are full-time employees of Dompé farmaceutici S.p.A. All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Mean total reparixin concentration versus time on day 1 (line with circles) and 21 (line with triangles). Results are presented as mean ± SEM
Fig. 2
Fig. 2
CSC evaluation in core biopsy samples by flow cytometry. a ALDH+ cells. b CD24−/CD44+ cells. Symbols represent individual patients. Patient 16’s day 21 core biopsy was taken on the day of surgery
Fig. 3
Fig. 3
CXCR1+ cell evaluation in core biopsy samples by flow cytometry. a All viable cells. b Tumor cells. Symbols represent individual patients. Patient 16’s day 21 core biopsy was taken on the day of surgery
Fig. 4
Fig. 4
Change from baseline to day 21 in CXCR1 expression on tumor cells by IHC. The percentage of patients with each score is presented. a Extent. b Intensity. x, no tumor found on the block
Fig. 5
Fig. 5
Change from baseline to day 21 in p62 expression on tumor cells by IHC. The percentage of patients with each score is presented. a Extent. b Intensity. x, no tumor found on the block

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Source: PubMed

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