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Published on: February 20, 2018
Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with Anti-Vascular Endothelial Growth Factor
Jean-Pierre Gagner1, Yasmeen Sarfraz1, Valerio Ortenzi1
1Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York.
Abstract:
Resistance to antiangiogenic therapy in glioblastoma (GBM) patients may involve hypoxia-induced expression of C-X-C motif chemokine receptor 4 (CXCR4) on invading tumor cells, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with POL5551 disrupts anti-vascular endothelial growth factor (VEGF) therapy-induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti-VEGF antibody B20-4.1.1. Brain tissue was analyzed for tumor volume, invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and MGCs. Glioma cells were evaluated for CXCR4 expression and polymorphism and POL5551's effects on CXCR4 ligand binding, cell viability, and migration. No CXCR4 mutations were identified. POL5551 inhibited CXCR4 binding to its ligand, stromal cell-derived factor-1α, and reduced hypoxia- and stromal cell-derived factor-1α-mediated migration dose-dependently but minimally affected cell viability. In vivo, B20-4.1.1 increased hypoxic foci and invasiveness, as seen in GBM patients receiving anti-VEGF therapy. Combination of POL5551 and B20-4.1.1 reduced both glioma invasiveness by 16% to 39% and vascular density compared to B20-4.1.1 alone in both glioma models. Reduced populations of GSCs and MGCs were also seen in CT-2A tumors. POL5551 concentrations, evaluated by mass spectrometry, were higher in tumors than in neighboring brain tissues, likely accounting for the results. Inhibition of CXCR4-regulated tumoral, stem cell, and immune mechanisms by adjunctive CXCR4 antagonists may help overcome antiangiogenic therapy resistance, benefiting GBM patients.
Insights
Targeting C-X-C motif chemokine receptor 4 (CXCR4) with POL5551 may overcome resistance to anti-angiogenic therapy in glioblastoma (GBM). This combination therapy reduced glioma invasiveness and key cell populations in preclinical models.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Resistance to anti-angiogenic therapy in glioblastoma (GBM) is a significant clinical challenge.
- Hypoxia-induced C-X-C motif chemokine receptor 4 (CXCR4) expression on tumor cells, immune cells, and glioma stem cells (GSCs) may drive this resistance.
- Vascular endothelial growth factor (VEGF) inhibitors can paradoxically increase tumor hypoxia and invasiveness.
Purpose of the Study:
- To investigate if antagonizing CXCR4 with POL5551 can overcome anti-VEGF therapy-induced resistance in glioblastoma models.
- To evaluate the impact of POL5551, alone and in combination with anti-VEGF therapy, on glioma growth, invasiveness, and cellular components.
Main Methods:
- Orthotopic glioma models (CT-2A and GL261) were treated with POL5551 and/or anti-VEGF antibody B20-4.1.1.
- Tumor tissues were analyzed for invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and macrophage/microglial cells (MGCs).
- In vitro studies assessed POL5551's effects on CXCR4 ligand binding, cell viability, and migration.
Main Results:
- POL5551 inhibited CXCR4 ligand binding and reduced hypoxia- and ligand-mediated migration dose-dependently.
- Anti-VEGF therapy (B20-4.1.1) increased glioma hypoxia and invasiveness.
- Combination therapy (POL5551 + B20-4.1.1) significantly reduced glioma invasiveness (16-39%) and vascular density compared to anti-VEGF therapy alone.
- Combination therapy also decreased GSC and MGC populations in CT-2A tumors.
Conclusions:
- Antagonizing CXCR4 with POL5551 can overcome resistance to anti-VEGF therapy in preclinical glioblastoma models.
- The combination strategy targets tumoral, stem cell, and immune mechanisms contributing to therapy resistance.
- Adjunctive CXCR4 inhibition holds promise for improving outcomes in GBM patients undergoing anti-angiogenic therapy.
