Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases

Abstract

The CXCR4/CXCL12 axis plays a role in cancer metastases, stem cell mobilization and chemosensitization. Proof of concept for efficient CXCR4 inhibition has been demonstrated in stem cell mobilization prior to autologous transplantation in hematological malignancies. Nevertheless CXCR4 inhibitors suitable for prolonged use as required for anticancer therapy are not available. To develop new CXCR4 antagonists a rational, ligand-based approach was taken, distinct from the more commonly used development strategy. A three amino acid motif (Ar-Ar-X) in CXCL12, also found in the reverse orientation (X-Ar-Ar) in the vMIP-II inhibitory chemokine formed the core of nineteen cyclic peptides evaluated for inhibition of CXCR4-dependent migration, binding, P-ERK1/2-induction and calcium efflux. Peptides R, S and I were chosen for evaluation in in vivo models of lung metastases (B16-CXCR4 and KTM2 murine osteosarcoma cells) and growth of a renal cells xenograft. Peptides R, S, and T significantly reduced the association of the 12G5-CXCR4 antibody to the receptor and inhibited CXCL12-induced calcium efflux. The four peptides efficiently inhibited CXCL12-dependent migration at concentrations as low as 10 nM and delayed CXCL12-mediated wound healing in PES43 human melanoma cells. Intraperitoneal treatment with peptides R, I or S drastically reduced the number of B16-CXCR4-derived lung metastases in C57/BL mice. KTM2 osteosarcoma lung metastases were also reduced in Balb/C mice following CXCR4 inhibition. All three peptides significantly inhibited subcutaneous growth of SN12C-EGFP renal cancer cells. A novel class of CXCR4 inhibitory peptides was discovered. Three peptides, R, I and S inhibited lung metastases and primary tumor growth and will be evaluated as anticancer agents.

First Experience with Chemokine Receptor CXCR4–Targeted PET Imaging of Patients with Solid Cancers

“…Similarly, the aggressiveness of a glioblastoma seems to correlate with its CXCR4 expression pattern (25), and a high accumulation of CXCR4 has been reported to be especially prevalent in breast carcinomas of high metastatic potential (5,6). In melanoma and NSCLC, the detection of high CXCR4 expression has even led to the preclinical development of antagonists, with promising results (26,27).…”

Molecular Pathways: Targeting the CXCR4–CXCL12 Axis—Untapped Potential in the Tumor Microenvironment

“…Finally, we have recently reported a new family of CXCR4 antagonists developed through a ligand-based approach (45,46). A three-residue segment identified in CXCL12 that was similar to, but in reverse order, to a peculiar inhibitory chemokine secreted by herpes virus 8 (HHV8) vMIP-II was the starting point (59,60).…”

“…The motif Ar1-Ar2-R, where Ar is an aromatic residue, constitutes the core of a cyclic peptide library evaluated for anti-CXCR4 activity. Three peptides (R, S, and I) identified as potent CXCR4 antagonists were demonstrated to reduce the development of metastases in in vivo models (45,46). Recent studies also demonstrated that peptides R, S, and I efficiently mobilize LY6G þ cells better and longer than AMD3100 and increase bone marrow cellularity, mainly of immature precursors, indicating an active hematopoietic stimulation.…”

CXCR4–CXCL12–CXCR7, TLR2–TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients

“…48 Albeit limited by the sample size, the present study demonstrated that high CXCR4 and Mut-KRAS identifies the worst prognostic group within a homogeneous cohort of mCRC with resectable liver metastases undergone to common neoadjuvant therapy. We speculate that the new class of CXCR4 antagonists recently developed 49 may be highly effective in Mut-KRAS CRLMs targeting CXCR4-positive cancer cells and improving T cell access by reducing tolerogenic effect and improving immune response in CRLM patients. ) 46-h continuous infusion; bevacizumab was administered at 5 mg/kg by i.v.…”