The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma.

Abstract

BACKGROUND:

Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity.

METHODS:

The effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40 mg/kg po qd), or PRX177561 (50 mg/kg po qd).

RESULTS:

The in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFβ1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF) and overall survival (OS), whereas the combination of PRX177561 with sunitinib showed a mild additive effect.

CONCLUSIONS:

The CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.

• Authors: Giovanni Luca Gravina, Andrea Mancini, Francesco Marampon, Alessandro Colapietro, Simona Delle Monache, Roberta Sferra, Flora Vitale, Peter J Richardson, Lee Patient, Stephen Burbidge, Claudio Festuccia
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 10 Issue 1 Pg. 5 (01 05 2017) ISSN: 1756-8722 [Electronic] England
• PMID: 28057017 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• CXCR4 protein, human
• Indoles
• Pyrroles
• Receptors, CXCR4
• Bevacizumab
• Sunitinib

Topics

• Angiogenesis Inhibitors
• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (pharmacology, therapeutic use)
• Brain (drug effects, metabolism)
• Brain Neoplasms (drug therapy)
• Cell Line, Tumor
• Drug Evaluation, Preclinical
• Drug Interactions
• Drug Synergism
• Glioblastoma (drug therapy)
• Heterografts
• Humans
• Indoles (pharmacology, therapeutic use)
• Mice
• Pyrroles (pharmacology, therapeutic use)
• Receptors, CXCR4 (antagonists & inhibitors)
• Sunitinib