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

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.

The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

“…In preclinical models of TNBC, IL-8 inhibition was shown to revert the mesenchymal phenotype, decrease MDSCs in the TME and enhance tumor cell killing by T and NK cells ( 202 ), providing the rational for combining IL-8 inhibitors with immunotherapy or chemotherapy. Reparixin, a small molecule inhibitor of the IL-8 receptors CXCR1 and CXCR2, has been tested in clinical trials (NCT01861054; NCT01861054) in HER2 − BC patients, reporting a 30% response rate in 27 patients and a decrease in the aldehyde dehydrogenase CSC marker in about 25% of patients ( 203 ). Besides cytokines, molecules involved in the production of the immunosuppressive metabolite adenosine represent promising targets for BC therapy.…”

Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

“…The authors used Reparixin in elaborate experiments and showed that it has anti-CSCs activity in breast cancer cell lines [ 349 ]. Reparixin has been in several clinical trials with mixed results from such studies ( Table 2 ) [ 350 , 351 ]. Further research involving blocking CXCR1/2 by Singh and colleagues also demonstrated decreased CSC activity in breast cancer [ 352 ].…”

Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer

“…It has reached phase 1 clinical trial in multiple myeloma ( Kaufman et al, 2013 ) and systemic lupus erythematosus ( Wallace et al, 2016 ), indicating no severe adverse effects. Apart from CD74, inhibitors against CXCL2 (Reparixin) and CXCL4 (Plerixafor) are also of interest for further investigation ( Steinberg and Silva, 2010 ; Goldstein et al, 2020 ). However, as MIF/CD74 pathway also plays an important role in wound repair by activating pro-survival and proliferative pathways that protects the host during injury ( Farr et al, 2020 ), complete inhibition of CD74 could cause some unpredictable side effects which need precaution.…”