CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti‐VEGF treatment or docetaxel in a transgenic mouse model

Abstract

CXCR4 is a chemokine receptor implicated in the homing of cancer cells to target metastatic organs, which overexpress its ligand, stromal cell-derived factor (SDF)-1. To determine the efficacy of targeting CXCR4 on primary tumor growth and metastasis, we used a peptide inhibitor of CXCR4, CTCE-9908, that was administered in a clinically relevant approach using a transgenic breast cancer mouse model. We first performed a dosing experiment of CTCE-9908 in the PyMT mouse model, testing 25, 50 and 100 mg/kg versus the scrambled peptide in groups of 8-16 mice. We then combined CTCE-9908 with docetaxel or DC101 (an anti-VEGFR2 monoclonal antibody). We found that increasing doses of CTCE-9908 alone slowed the rate of tumor growth, with a 45% inhibition of primary tumor growth at 3.5 weeks of treatment with 50 mg/kg of CTCE-9908 (p 5 0.005). Expression levels of VEGF were also found to be reduced by 42% with CTCE-9908 (p 5 0.01). In combination with docetaxel, CTCE-9908 administration decreased tumor volume by 38% (p 5 0.02), an effect that was greater than that observed with docetaxel alone. In combination with DC101, CTCE-9908 also demonstrated an enhanced effect compared to DC101 alone, with a 37% decrease in primary tumor volume (p 5 0.01) and a 75% reduction in distant metastasis (p 5 0.009). In combination with docetaxel or an anti-angiogenic agent, the anti-tumor and anti-metastatic effects of CTCE-9908 were markedly enhanced, suggesting potentially new effective combinatorial therapeutic strategies in the treatment of breast cancer, which include targeting the SDF-1/CXCR4 ligand/receptor pair.Although the survival of patients with breast cancer has improved in recent years, further progress will require a better understanding of the metastatic process, which is the underlying cause of breast cancer mortality. The process of metastasis has been divided into several stages including the invasion of the primary tumor, intravasation into the bloodstream, circulation, extravasation and proliferation at the distant metastatic site. 1 A recently proposed model that explains the process of extravasation of tumor cells from the peripheral circulation into target organs of metastasis is the chemokine-receptor model. Muller et al. showed that chemokines are overexpressed by those organs to which cancer metastasizes and serves to attract cancer cells which express their receptor, 2 analogous to their function in recruiting inflammatory cells to sites of tissue injury. They identified the chemokine/receptor pair, stromal cell-derived factor (SDF)-1/CXCR4 as a candidate metastasis promoter in breast cancer. 2 We have since shown that CXCR4 is overexpressed in 67% of breast cancer samples, that elevated expression of CXCR4 carries a poor prognosis, and that CXCR4 expression is strongly associated with human epidermal growth factor receptor 2 (HER2) expression in these tumors. 3 Therefore, it appears plausible that inhibition of CXCR4 activity may hinder the metastatic process. Moreover,

Functional Roles of Long Non-coding RNA in Human Breast Cancer

“…In anthropogenic of undifferentiated embryonic stem cells, some mRNAs play an important role in maintaining pluripotent of stem cells, due to lack of NEAT1 and paraspeckles, for example Lin28 which can be quickly out of the nucleus after transcription, and then translate stem cells needed Lin28 protein (Chen et al, 2009) but when LSINCT5 overexpress, there are opposite effect, which prompt NEAT1 has a decisive role in anthropogenic embryonic stem cell fate. In addition, study also found other genes CXCR4, a chemokine receptor in the GPCR gene family, which is a crucial breast cancer marker related with invasion and metastasis was significantly affected by knocking down the expression of LSINCT5 (Hassan et al, 2011). Thus it can be seen that LSINCT5 reinforce cellular proliferation and involve in multiple processes, which let LSINCT5 has potential value as a marker to diagnose breast cancer or a target for tumor treatment.…”

High expression of SDF‑1 and VEGF is associated with poor prognosis in patients with synovial sarcomas

“…Antigen retrieval was performed by microwaving the array in sodium citrate buffer at 95˚C for 10 min. Subsequently, the samples were blocked in normal goat serum (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) at 37˚C for 1 h Immunohistochemical staining was performed according to a routine protocol (18). Samples were incubated at 37˚C for 1 h with rabbit anti-human SDF-1 (cat.…”

“…Previous studies have demonstrated that overexpression of VEGF is essential for the growth and survival of many types of cancer cells (18). In addition, high levels of VEGF are associated with unfavorable survival rates in patients with SS (18,19). The present study aimed to evaluate the expression patterns of SDF-1 and VEGF in samples from SS tissue and determine the potential association between SDF-1 and VEGF expression and patient clinical outcomes.…”

“…Previous studies have demonstrated that overexpression of VEGF is essential for the growth and survival of many types of cancer cells (18). In addition, high levels of VEGF are associated with unfavorable survival rates in patients with SS (18,19).…”

Structure-based design of inhibitors of CXCR4.

“…CTCE-9908 has been demonstrated to function as a CXCR4 antagonist and decrease metastasis of breast cancer cells [177,178], osteosarcoma cells [176] and melanoma cells [176] Asp262 on extracellular loop 3 [200]. Photolabeling studies of radiolabeled T140…”