CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer

Abstract

The SDF-1-receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow disseminated tumor cells (DTC) negative patients at high risk for metastasis and death. The Protein Epitope Mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared to single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we utilized a “chemotherapy framing” dosing strategy. When administered shortly before and after eribulin treatment, 3 doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases.

Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with Anti–Vascular Endothelial Growth Factor Therapy–Induced Glioma Dissemination

“…The effects of POL5551 do not appear to be because of direct cytotoxicity as incubation with various concentrations of POL5551 (1 nmol/L to 1 mmol/L) had little effect on the viability of CT-2A, GL261, and U87 glioma cells ( Figure 8C), in agreement with data obtained in adherent cultures of breast cancer cells treated with POL5551. 54 In Boyden chamber assays, increasing concentrations of (Figure 8, DeF), consistent with the inhibitory effect of POL5551 on the migration of breast cancer cells. 54 The apparently greater sensitivity of GL261 cell migration to POL5551 is consistent with the larger inhibitory effect of POL5551 on the invasiveness of GL261 glioma in vivo compared to CT-2A glioma (Figure 1, C and D).…”

“…54 In Boyden chamber assays, increasing concentrations of (Figure 8, DeF), consistent with the inhibitory effect of POL5551 on the migration of breast cancer cells. 54 The apparently greater sensitivity of GL261 cell migration to POL5551 is consistent with the larger inhibitory effect of POL5551 on the invasiveness of GL261 glioma in vivo compared to CT-2A glioma (Figure 1, C and D). The migration of CT-2A ( Figure 8, D and F) and GL261 cells ( Figure 8E) increased approximately twofold under 24-hour hypoxic conditions (P < 0.001) and to a lesser extent in response to SDF-1a.…”

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

“…The murine BALB/c 4T1 triple-negative breast cancer cell line was purchased from ATCC, as previously described (31). Human MDA-MB-231 breast cancer cells (HTB-26) were purchased from ATCC (30).…”

“…The MTT assay was performed as described previously (31). Signal intensity normalized to 0% for the viability of cells at time of drug addition, and 100% for the viability of vehicle control treated cells at 72 hr.…”

ATRAIDregulates the action of nitrogen-containing bisphosphonates on bone

“…multiple myeloma patients who did or did not suffer osteonecrosis of the jaw (ONJ) when taking N-BPs 41 ; and breast cancer patients with bone marrow disseminated tumor cells (DTC) which 6 reoccurred or the patient died less than 1000 days vs. greater than 2500 days following initiation of zolendronate treatment 42 ( Fig. 1i, and Supplementary Fig.…”