New research suggests that inhibiting platelet-derived growth factor (PDGF), which regulates cell growth and division, could help overcome resistance to anti–vascular endothelial growth factor treatment in glioblastoma multiforme.
The anti—vascular endothelial growth factor (anti-VEGF) agent bevacizumab (Avastin), for which a biosimilar (Mvasi) has been approved in the United States, is used to treat a variety of malignancies, including the highly vascularized malignancy glioblastoma.
Glioblastoma cells secrete VEGF, which induces the formation of a dysfunctional vascular system in the tumor, and while ongoing treatment with bevacizumab leads to regression of tumor vasculature, the benefits of bevacizumab in grade IV glioma, or glioblastoma multiforme (GBM), have been small. The slight nature of these benefits may be due to insufficient eradication and inhibition of tumor-associated endothelial cells. Now, new research suggests that inhibiting platelet-derived growth factor (PDGF), which regulates cell growth and division, could help overcome resistance to anti-VEGF therapy in GBM.
Recent clinical studies have shown greater therapeutic efficacy by dual antagonism of PDGF and VEGF in treating age-related macular degeneration, and a research team led by Yi Fan, MD, PhD, investigated whether such a strategy in treating glioblastoma might yield similarly improved benefits.
The researchers analyzed specimens and found that VEGF receptor expression was reduced in tumor-derived endothelial cells in both human and mouse GBM endothelial cells. Furthermore, they found that PDGF mediates endothelial-mesenchymal transformation to induce resistance to anti-angiogenic treatment by downregulating expression of VEGF receptor 2 (VEGFR2).
In a mouse model, endothelial cell-specific deletion of PDGF receptor beta was able to sensitize VEGF blockade treatment, and the anti-VEGF agent was then able to efficiently eradicate endothelial cells, leading to abrogated tumor growth and improved survival (+35 days) in GBM-bearing mice.
“Pharmacological inhibition or genetic ablation of PDGF signaling robustly sensitizes anti-VEGF/VEGFR2 treatment in GBM. As such, combination of vascular de-transformation with conventional anti-angiogenic therapy may offer exciting opportunities to treat malignant cancer,” the researchers concluded.
Liu T, Ma W, Xu H, et al. PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nature Communications. 2018;9:3439. doi: 10.1038/s41467-018-05982-z.