Enhancing the efficacy of VEGF inhibitors by co-inhibition of HIF in the treatment of glioblastoma.

Glioblastoma is the most aggressive and most common grade 4 tumor of the central nervous system (CNS). Despite standard treatments such as surgical resection and chemoradiotherapy, overall survival (OS) usually does not exceed 14-16 months in clinical trials, and no improvement in OS has been demonstrated even with the use of vascular endothelial growth factor A (VEGFA) inhibitors such as bevacizumab. In response to radiotherapy, hypoxia-inducible factor (HIF) stabilization leads to activation of alternative pro-angiogenic pathways, increasing VEGF expression and tumor angiogenesis. Several clinical trials evaluating HIF-2α inhibitors as monotherapy in the absence of concurrent VEGF inhibition, have similarly failed to demonstrate a significant improvement in OS outcomes. This review provides a perspective on the combined use of VEGF and HIF inhibitors, and provides an insight into future studies.