Collectively, our findings highlight the significance of a selective CXCR2+/CD11b+/Gr-1+ subset myeloid cells in favoring the development of CRLM with NAFLD background, and identify a pharmaceutic medicine which is already available for the clinical trials and potential treatment.

However, these effects were reversed by the CXCL2-CXCR2 inhibitor SB225002. In summary, this study suggests that Fn contributes to OSCC progression by promoting tumor cell proliferation, macrophage recruitment, and M2 polarization. Simultaneously, the enhanced CXCL2-mediated crosstalk between OSCC cells and macrophages plays a vital role in the pro-cancer effect of Fn.

P2, N=350, Recruiting, Eli Lilly and Company | Trial completion date: Mar 2026 --> Jul 2026 | Trial primary completion date: Apr 2025 --> Aug 2025

P1/2, N=50, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Overall, we demonstrated that TAMs boosted PDAC cell glycolysis through the IL-8/STAT3/GLUT3 signaling pathway. Our cumulative findings suggest that the abrogation of TAM-induced tumor glycolysis by reparixin might exhibit an antitumor impact and offer a potential therapeutic target for PDAC.

Taken together, our study implicates CXCL1 as a critical role in ERBC growth and metastasis via crosstalk with fibroblast and cotargeting CXCR1/2 and CDK4/6 could potentially overcome endocrine resistant breast cancer.

In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic...Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future.

P1, N=20, Recruiting, University of Rochester | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925).

P2, N=53, Not yet recruiting, Syntrix Biosystems, Inc.

P2, N=350, Recruiting, Eli Lilly and Company | Phase classification: P2b --> P2 | Trial completion date: Jul 2026 --> Mar 2026 | Trial primary completion date: Jul 2025 --> Apr 2025

SB225002 (a CXCR2 inhibitor) treatment significantly impairs SiHa cell-induced neutrophil migration...Conditioned medium of tumor-associated neutrophils (TANs) can drastically enhance cervical cancer cell growth in vitro and in vivo. The CXCLs-CXCR2 axis is critical in neutrophil recruitment and tumor cell proliferation in the cervical cancer microenvironment.

P1/2, N=53, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1/2, N=340, Active, not recruiting, AstraZeneca | Phase classification: P1b/2 --> P1/2 | Trial completion date: Dec 2023 --> Mar 2025

P2, N=26, Recruiting, Icahn School of Medicine at Mount Sinai

P1, N=77, Recruiting, Syntrix Biosystems, Inc. | Trial completion date: Dec 2023 --> Jun 2026 | Trial primary completion date: Jul 2023 --> Jun 2025

P1/2, N=50, Not yet recruiting, National Cancer Institute (NCI)

Targeting CAF-derived IL-8 may defeat PD-L1 upregulation-mediated immune resistance in GC cells, which provides a novel approach to improve the immunotherapeutic efficacies of patients with GC.

P2b, N=350, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P1, N=151, Recruiting, Syntrix Biosystems, Inc. | N=64 --> 151 | Trial completion date: Mar 2024 --> Mar 2029 | Trial primary completion date: Aug 2023 --> Mar 2028

Here, we report the rational design, synthesis, and pharmacological evaluation of a series of fluorescent NAMs, based on navarixin (2), which display high affinity and preferential binding for CXCR2 over CXCR1. We demonstrate their application in fluorescence imaging and NanoBRET binding assays, in whole cells or membranes, capable of kinetic and equilibrium analysis of NAM binding, providing a platform to screen for alternative chemophores targeting these receptors.

DL-1MT and SB225002 were administered for 30 days in two regimens (R1 and R2) based on combination and single therapy approaches to inhibit IDO-1 and CXCR-2, respectively...Furthermore, the proliferation diminished, and apoptosis and intra-tumoral CD8 T cells increased. In conclusion, the combined inhibition of IDO-1 and CXCR-2 is helpful in the antitumor response against preclinical cervical cancer.

P2, N=25, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

L-NIL treated tumor-bearing mice exhibited reductions in tumor-infiltrating myeloid cells and in plasma Cxcl5 levels, and attenuated primary tumor growth with increased apoptosis and decreased proliferation. Blocking Cxcl5 with an antagonist of its receptor Cxcr2, SB225002, also reduced SCC lung metastasis.

The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.

P2, N=25, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: May 2026 --> Sep 2026 | Trial primary completion date: May 2026 --> Sep 2026

Our findings reveal that blocking GCMSCs-derived IL-8/CXCR2 pathway decreasing PD-L1 expression and lactate production, improving antitumor efficacy of anti-PD-1 immunotherapy, may be of value for the treatment of advanced gastric carcinoma.

P1/2, N=30, Terminated, Institute of Cancer Research, United Kingdom | N=86 --> 30 | Trial completion date: Oct 2023 --> Nov 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2023 --> Sep 2022; Discontinuation of production of IMP

Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.

We also investigated the effect of adding SX682, a small-molecule inhibitor of CXCR1/2 known to reduce MDSC trafficking to tumor microenvironment, to our therapeutic approach...Treatment with HMGN1, FSL-1, R848, and anti-CTLA4 antibody increased the number of infiltrating CD4+ and CD8+ effector/memory T cells in both tumors and draining lymph nodes and triggered the generation of 4T1-specific cytotoxic T lymphocytes (CTLs) in the draining lymph nodes. Thus, we developed a potentially curative immunotherapeutic regimen consisting of HMGN1, FSL-1, R848, plus a checkpoint inhibitor for TNBC, which does not rely on the administration of chemotherapy, radiation, or exogenous tumor-associated antigen(s).

Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis.

Conversely, CXCR2 inhibition with AZD5069 led to reduced CD4 proliferation and PD-1 expression.Summary/ This study further highlights the importance of immune evasion in mediating AML relapse following AHSCT. This study further highlights the importance of immune evasion in mediating AML relapse following AHSCT. The chemokines CXCL2 and CXCL8 were identified as potential mediators of this process and may provide prospective targets to enhance the GvL effect to prevent or treat post-AHSCT relapse. Diagram Description automatically generated Chemokine, Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant

P1/2, N=12, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Oct 2021 --> Feb 2023

30 female C57BL/6 mice were randomly divided into the PBC model group (PBC group), reparixin intervention group (Rep group), and blank control group (Con group) in an in vivo experiment...Compared with the IL-8 group, the proliferation of human intrahepatic cholangiocyte epithelial cells, NF-κB and ERK pathway-related proteins, and inflammatory indicators were significantly reduced in the Rep group (P < 0.05). The CXCR1/CXCL8 axis can regulate the abnormal proliferation of bile duct epithelial cells in PBC, and its mechanism of action may be related to NF-κB and ERK pathways.

P1/2, N=10, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jan 2024 --> Apr 2023 | Trial primary completion date: Jan 2024 --> Apr 2023

Recombinant human IL-8 (rhIL-8) reversed the inhibitory effect of Dicer on proliferation (P < .01), migration (P = .003), and invasion (P = .001), whereas IL-8 inhibitor of reparixin enhanced inhibitory effect of Dicer on proliferation (P < .05), migration (P = .008), and invasion (P = .000). Animal experiments also demonstrated that Dicer cooperated with lenvatinib to inhibit the growth of HCC tumors (P < .05). Dicer cooperated with lenvatinib to inhibit HCC growth via downregulating IL-8, and Dicer displayed its potential capability to enhance the anti-tumor effect of lenvatinib.

In this study, we analyzed the immune contexture of advanced HCC patients before and after pembrolizumab treatment to investigate the role of myeloid IL-8 in ICB-resistance mechanism and aim to intervene the IL-8 pathway through inhibition of its receptor by a clinical in-use CXCR2 antagonist...Therapeutic efficacy of CXCR2 pathway inhibition by AZD5069 in potentiating ICB response was evaluated in our ICB-resistant orthotopic mouse model which is generated by serial in vivo passaging of anti-PD-L1 residual tumor... We demonstrated the importance of myeloid IL-8/CXCR2 pathway in ICB-resistance from our advanced HCC cohort which paved way for IL-8 to become a novel prognostic target for immunotherapy. Blocking CXCR2 could reduce MDSC trafficking and overcome ICB-resistance in our pre-clinical HCC model, suggesting a promising combination regimen in future development.

Hence, we provide an overview containing the discovery history, protein structure, signaling pathways, biological functions, structure-activity relationships and clinical significance of CXCR2 antagonists in inflammatory diseases and cancers. According to the latest development and recent clinical progress of CXCR2 small molecule antagonists, we speculated that CXCR2 can be used as a biomarker and a new target for diabetes and that CXCR2 antagonists may also attenuate lung injury in coronavirus disease 2019 (COVID-19).

Mechanistically, we found that redox effector factor-1 (Ref-1) secreted by breast cancer cells activated hypoxia inducible factor-1α (HIF-1α) expression and inhibited reactive oxygen species (ROS) production in Schwann cells, ultimately inducing CXCL2 expression in Schwann cells. In brief, the present study expands new insights into cancer pain mechanisms from promising animal models to provide new strategies for the control of cancer pain.

The primary objectives are to determine safety profile, recommended phase 2 dose, clinical activity & 6m ctDNA clearance rate in CRC pts with MRD following 6m of SX-682 + Nivolumab on Arm B. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140.

Furthermore, C-X-C motif chemokine receptor 2 (CXCR2) antagonist SB225002 enhanced the docetaxel (DTX) effects on tumor growth by decreasing BCSCs in CCL20-expressing tumors. These findings elucidated how CCL20 modulated the TME to promote cancer development, indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer, especially in CCL20-expressing breast cancer.