Regorafenib and glioblastoma: a literature review of preclinical studies, molecular mechanisms and clinical effectiveness

Abstract

Glioblastoma IDH wild type (GBM) is a very aggressive brain tumour, characterised by an infiltrative growth pattern and by a prominent neoangiogenesis. Its prognosis is unfortunately dismal, and the median overall survival of GBM patients is short (15 months). Clinical management is based on bulk tumour removal and standard chemoradiation with the alkylating drug temozolomide, but the tumour invariably recurs leading to patient's death. Clinical options for GBM patients remained unaltered for almost two decades until the encouraging results obtained by the phase II REGOMA trial allowed the introduction of the multikinase inhibitor regorafenib as a preferred regimen in relapsed GBM treatment by the National Comprehensive Cancer Network (NCCN) 2020 Guideline. Regorafenib, a sorafenib derivative, targets kinases associated with angiogenesis (VEGFR 1-3), as well as oncogenesis (c-KIT, RET, FGFR) and stromal kinases (FGFR, PDGFR-b). It was already approved for metastatic colorectal cancers and hepatocellular carcinomas. The aim of the present review is to focus on both the molecular and clinical knowledge collected in these first three years of regorafenib use in GBM.

Keywords: glioblastoma IDH-wild type; glioma stem cells; multikinase inhibitor; regorafenib; therapy.

Graphical abstract

Figure 1.

Current therapeutic approach for GBM patients. First-line treatment for GBM patients is based on surgery and adjuvant chemoradiation with the alkylating agent temozolomide. At tumour relapse, second-line treatment is lomustine, the humanised monoclonal antibody bevacizumab, which targets vascular endothelial growth factor (approved limiting to US, Japan and China) and the recently approved regorafenib. Created with Biorender.com.

Figure 2.

Molecular structure of regorafenib. Created with Biorender.com

Figure 3.

Molecular targets of regorafenib. Regorafenib targets stromal (FGFR, PDGFR), angiogenic (VEGFRs, Tie-2) and oncogenic kinases (RET, KIT). Created with Biorender.com.